Ester derivatives

ABSTRACT

This invention relates to compounds which exhibit selective muscarinic M 3  receptor antagonism, have little side effects, are suitable for inhalation therapy and are useful as treating agents of respiratory system diseases, of the general formula (I); 
     
       
         
         
             
             
         
       
     
     [in which A signifies a group expressed by a formula (a 0 ) or (b 0 ); 
                         
Ar signifies optionally substituted aryl or heteroaryl; B 1  and B 2  signify aliphatic hydrocarbon; R 1  signifies fluorine-substituted cycloalkyl; R 2 , R 3  and R 4  signify lower alkyl, single bond or alkylene bonded to B 1 , or R 2  and R 3  are united to signify alkylene; R 5  and R 7  signify hydrogen, lower alkyl, or a single bond or alkylene bonded to B 2 ; R 6  signifies hydrogen, lower alkyl or a group expressed as —N(R 8 )R 9 ; and X −  signifies an anion].

This application is a divisional of Ser. No. 10/983,613, filed Nov. 9,2004 now U.S. Pat. No. 7,192,969, which is a divisional of Ser. No.10/332,617, now U.S. Pat. No. 6,846,835, filed Jan. 10, 2003, which is aU.S. national stage of International Application No. PCT/JP01/05987,filed Jul. 10, 2001.

TECHNICAL FIELD

This invention relates to novel ester derivatives, processes forpreparing them, pharmaceutics containing them and their use asmedicines, especially for the treatment of various diseases of therespiratory system.

BACKGROUND ART

Antagonism to muscarinic receptors are known to cause bronchodilation,gastrointestinal hypanakinesis, gastric hyposecretion, dry mouth,mydriasis, suppression of bladder contraction, hypohydrosis, tachycardiaand the like [cf. “Basic and Clinical Pharmacology, 4th ed., (APPLETON &LANGE), pp. 83-92, (1989); and Drug News & Perspective, 5(6), pp.345-352 (1992)].

It has been made clear through recent studies that there are at leastthree subtypes of muscarine receptors (M₁ receptors, M₂ receptors and M₃receptors); which receptors are present in tissues or organs atdifferent distribution patterns. M₁ receptors are present mainly on thebrain; M₂ receptors, on the heart; and M₃ receptors, on the smoothmuscles and glandular tissues. Whereas, all of the large number ofcompounds heretofore known to exhibit antagonism to muscarinic receptorsantagonize these three subtypes of muscarinic receptors non-selectively.Consequently, in oral administration of these compounds as therapeuticor prophylactic agents for treatment of diseases of, for example, therespiratory system, in addition to such side effects as dry mouth,nausea and mydriasis, serious side effects associated with the centralnervous system, such as dementia, induced particularly by M₁ receptorsand those associated with the heart, such as tachycardia caused by M₂receptors present problems.

Currently, administration by inhalation of non-selective muscarineantagonists as therapeutic or prophylactic agents for respiratorydiseases is clinically applied. However, those medicines are subject tothe problems that durability of their action is short and theirinhalation plural times per day is necessary, and also that they havesuch side effects as tachycardia and dry mouth attributable to thenon-selectivity of said receptors.

As compounds having a structure resembling that of the compounds of thepresent invention, for example, those described in JP-Hei 1(1989)-131145A or in Farmaco, Vol. 47, No. 9, pp. 1133-1147 (1992) canbe cited, which, however, neither concretely disclose nor suggest thecompounds of the present invention.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide treating agents ofdiseases associated with muscarine M₃ receptors, which exhibit highlyselective antagonism to muscarine M₃ receptors but little side effectand hence are safe and effective.

We have discovered that the compounds represented by a general formula(I):

[in which A signifies a group expressed by a formula (a₀) or (b₀);

Ar signifies aryl or heteroaryl optionally having substituent(s)selected from a group consisting of halogen, lower alkyl, lower alkenyland lower alkoxy; B¹ and B² signify, independently of each other,straight chain, branched chain and/or cyclic portion-containing C₂-C₁₀saturated or unsaturated aliphatic hydrocarbon which may have hydroxylgroup(s) and/or be interrupted with nitrogen atom(s); R¹ signifies afluorine-substituted C₄-C₆ cycloalkyl optionally having hydroxylgroup(s); R², R³ and R⁴ signify, either independently of each other, alower alkyl optionally having substituent(s) selected from a groupconsisting of phenyl and cycloalkyl, or R² and R³ together signify aC₂-C₅ alkylene which may be interrupted with oxygen; or R⁴ signifies asingle bond or a C₁-C₃ alkylene binding to a bindable optional site onB¹; R⁵ signifies hydrogen or a lower alkyl optionally havingsubstituent(s) selected from a group consisting of phenyl and cycloalkyland R⁷ signifies hydrogen or a lower alkyl, or either one of R⁵ and R⁷signifies a single bond or a C₁-C₃ alkylene binding to a bindableoptional site on B²; R⁶ signifies hydrogen, lower alkyl or a grouprepresented by —N(R⁸)R⁹; R⁸ and R⁹ signify, independently of each other,hydrogen or lower alkyl; and X⁻ signifies an anion] exhibit highlyselective antagonism to muscarine M₃ receptors and hence have littleside effect and are safe. Furthermore, they also exhibit excellentpharmacological effect and durability of the action in inhalationtherapy. Accordingly, we found the compounds very useful for treatingvarious diseases associated with muscarine M₃ receptors, e.g.,respiratory diseases such as chronic obstructive pulmonary diseases,chronic bronchitis, asthma, chronic respiratory tract obstruction,fibroid lung, pulmonary emphysema and rhinitis. The present invention iswhereupon completed.

This invention relates to the compounds represented by the generalformula (I) or salts thereof, and their production processes and theirutility.

The invention furthermore relates to the compounds which areintermediate products of the compounds represented by the generalformula (I) and exhibit highly selective antagonism to muscarine M₃receptors, i.e., the compounds represented by a general formula (II)

[in which A^(p) signifies a group represented by a formula (a_(p0)) or(b_(p0))

R²⁰ signifies hydrogen or a lower alkyl optionally having substituent(s)selected from a group consisting of phenyl and cycloalkyl; R⁴⁰ signifieslower alkyl which may have substituent(s) selected from a groupconsisting of phenyl and cycloalkyl, or a single bond or a C₁-C₃alkylene group binding to a bindable optional site on B¹; and Ar, B¹,B², R¹ and R⁵ have the earlier given significations] and salts thereof.

Hereinafter we will explain the meanings of the terms used in thisspecification and describe the present invention in further details.

“Halogen” means fluorine, chlorine, bromine and iodine atoms.

“Lower alkyl” means C₁-C₆ straight chain or branched alkyl groups,examples of which include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexylgroups.

“Lower alkenyl” means C₂-C₆ straight chain or branched alkenyl groups,examples of which include vinyl, 1-propenyl, 2-propenyl, isopropenyl,3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl,1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl,2-methyl-1-propenyl, 3-methyl-2-butenyl and 4-pentenyl groups.

“Lower alkoxy” means C₁-C₆ straight chain or branched alkoxy groups orC₁-C₃ alkylenedioxy groups, examples of which include methoxy, ethoxy,propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy,pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, methylenedioxy,ethylenedioxy and trimethylenedioxy groups.

“Aryl” means C₆-C₁₁ aryl groups, examples of which include phenyl andnaphthyl groups.

“Heteroaryrl” means 5- or 6-membered monocyclic heteroaryl groupscontaining one or two same or different hetero atoms selected from agroup consisting of nitrogen, oxygen and sulfur atoms, or condensedring-type heteroaryl groups formed by condensation of one of saidmonocyclic heteroaryl groups with one of aforesaid aryl groups, or bymutual condensation of same or different monocyclic heteroaryl groups asabove-explained, examples of which include 2-pyridyl, 3-pyridyl,4-pyridyl, 2-thiazolyl, 4-thiazolyl, 2-thienyl, 3-thienyl, 1-imidazolyl,2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-furyl, 3-furyl,2-pyrrolyl, 3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 2-quinolinyl, 2-benzothienyland 2-indolyl groups.

“Straight chain, branched chain and/or cyclic portion-containing C₂-C₁₀saturated or unsaturated aliphatic hydrocarbon which may have hydroxylgroup(s) and/or be interrupted with nitrogen atom(s)” means straightchain, branched chain and/or cyclic portion-containing C₂-C₁₀ saturatedor unsaturated aliphatic hydrocarbon groups which have 1, 2 or more,preferably 1, hydroxyl group(s) on optional, substitutable position(s)on such saturated or unsaturated aliphatic hydrocarbon group or do nothave them and, furthermore, which are interrupted with 1, 2 or more,preferably 1, nitrogen atom(s) at interruptable, optional position(s) inthe hydrocarbon chain of said group or not interrupted, examples ofwhich include those groups represented by formulae (11)

or those of the above formulae which however have 1, 2 or more,preferably 1, hydroxyl group(s) at optional, substitutable position(s)thereof.

“Cycloalkyl” means C₃-C₇ cycloalkyl groups, examples of which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

“C₂-C₅ alkylene which may be interrupted with oxygen” means C₂-C₅alkylene groups which are interrupted with 1, 2 or more, preferably 1,oxygen atom(s) at interruptable, optional site(s) in said alkylene chainor not interrupted, examples of which include ethylene, trimethylene,tetramethylene, pentamethylene, 2-oxatetramethylene, 2-oxapentamethyleneand 3-oxapentamethylene groups.

Examples of “C₁-C₃ alkylene” include methylene, ethylene andtrimethylene groups.

Definition of each of B¹¹ and B¹² (or B²¹ and B²²), “C₁-C₆ saturated orunsaturated aliphatic hydrocarbon which may be mutually crosslinked”means C₁-C₆ saturated or unsaturated aliphatic hydrocarbon groups whichare not mutually crosslinked or have a mutual single bond or C₁-C₄crosslinkage.

Examples of said C₁-C₆ saturated or unsaturated aliphatic hydrocarbongroups are divalent or trivalent groups formed of, e.g., methane,ethane, propane, propene, butane, 1-pentene, hexane or the like. Morespecifically, they form together with nitrogen atom adjacent to thesegroups, when they do not have crosslinkage, monocyclic groupscomprising, e.g., aziridine ring, azetidine ring, pyrrolidine ring,piperidine ring, tetrahydropyridine ring or 2-vinylpiperidine ring;whereas, when they have crosslinkage, bicyclic groups comprising, e.g.,8-azabicyclo [3.2.1] octane ring, 3-azabicyclo [3.3.0] octane ring or3-azabicyclo [3.3.1] nonane ring.

[Anion] is to make a pair with the ammonium ion on a compound of thepresent invention to electrically neutralize said compound and is notsubject to any particular limitation so long as it is pharmaceuticallyacceptable. For example, anions formed from halogen, inorganic acid,organic sulfonic acid, carboxylic acid and the like, such as

F⁻, Cl⁻, Br⁻, I⁻,

${\frac{1}{2}{SO}_{4}^{2 -}},$HSO₄ ⁻,

${\frac{1}{3}{PO}_{4}^{3 -}},{\frac{1}{2}{HPO}_{4}^{2 -}},$H₂PO₄ ⁻, NO₃ ⁻, CH₃OSO₃ ⁻, CH₃SO₃ ⁻, CH₃CH₂SO₃ ⁻,

HCOO⁻, CH₃COO⁻,

may be used.

Salts of the compounds represented by the general formula (I) means, forexample, customary pharmaceutically acceptable salts of the compounds inwhich “A” in the formula stands for the groups expressed by formula(b₀). As such salts, for example, inorganic acid salts such ashydrochloride, sulfate, nitrate, phosphate and perchlorate; organiccarboxylic acid salts such as benzoate, maleate, fumarate, succinate,tartarate, citrate and ascorbate; and organic sulfonic acid salts suchas methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate andp-toluenesulfonate may be named.

“Treating agent” means medicines which are applied to patients sufferingfrom various diseases for therapeutic and/or prophylactic purposes.

“Inhalant” means those medicines per se well known in the medical field,which are in the form of being used by inhaling through the respiratoryorgan at the application time, such as aerosol, inhalant powder,inhalant liquid, and the like.

The compounds of the present invention in occasions have stereoisomersor tautomers such as optical isomers, diastereoisomers or geometricalisomers, depending on configuration of substituents. The inventionincludes all of such stereoisomers, tautomers and their mixtures withinits scope.

With the view to disclose the compounds of the invention still morespecifically, the symbols and signs are explained in further detailshereunder, citing preferred specific examples.

A signifies the groups expressed by the formulae (a₀) or (b₀)

B¹ and B² signify, independently of each other, straight chain, branchedchain and/or cyclic portion-containing C₂-C₁₀ saturated or unsaturatedaliphatic hydrocarbon which may have hydroxyl group(s) and/or beinterrupted with nitrogen atom(s).

As B¹, for example, those groups represented by formulae (12)

are convenient, in particular, those represented by formulae (13) arepreferred.

As B², for example, those groups represented by formulae (14)

are convenient, in particular, that represented by a formula (15) ispreferred.

In the formula (a₀), R², R³ and R⁴ signify, either independently of eachother, a lower alkyl optionally having substituent(s) selected from agroup consisting of phenyl and cycloalkyl, or R² and R³ together signifya C₂-C₅ alkylene which may be interrupted with oxygen, or R⁴ signifies asingle bond or C₁-C₃ alkylene binding to a bindable optional site on B¹,and X⁻ signifies an anion.

Said “lower alkyl optionally having substituent(s) selected from a groupconsisting of phenyl and cycloalkyl” defining R², R³ and R⁴ signifyaforesaid unsubstituted lower alkyl or the lower alkyl havingsubstituent(s) on substitutable, optional position(s), said 1, 2 ormore, preferably 1, substituent(s) which are the same or different andselected from the group consisting of phenyl and cycloalkyl.

As cycloalkyl which can be present as the substituent, for example,cyclohexyl, cycloheptyl and the like are preferred.

Where R², R³ or R⁴ are “lower alkyl”, for example, methyl, ethyl,propyl, isopropyl and the like are preferred.

Accordingly, where R², R³ and R⁴ represent, independently of each other,“lower alkyl optionally having substituent(s)”, specific examplesinclude methyl, ethyl, propyl, isopropyl, cyclohexylmethyl,cycloheptylmethyl, benzyl and the like, methyl being preferred.

As “C₂-C₅ alkylene which may be interrupted with oxygen” formed by R²and R³ together, for example, tetramethylene, pentamethylene,3-oxapentamethylene and the like are convenient. In particular,3-oxapentamethylene group is preferred.

Where R⁴ binds to a bindable optional site on B¹, single bond ormethylene or ethylene are preferred as such R⁴.

In preferred embodiments of R², R³ and R⁴, for example, R² and R³ eitherstand for, independently of each other, lower alkyl optionally havingsubstituent(s) selected from the group consisting of phenyl andcycloalkyl; or R² and R³ together signify a C₂-C₅ alkylene which may beinterrupted with oxygen and R⁴ signifies a single bond or C₁-C₃ alkylenewhich binds to a bindable optional site on B¹.

As X⁻, for example, anions formed from halogen atoms such as

Cl⁻, Br⁻,

and the like are preferred.

More specific, preferred embodiments of A in the general formula (I) inwhich A is a group represented by the formula (a₀) include, for example,a group expressed by a formula (a₁)

[in which B¹¹ and B¹² are, independently of each other, C₁-C₆ saturatedor unsaturated aliphatic hydrocarbon groups, which may be mutuallycrosslinked; k is 0, 1 or 2; and R², R³ and X⁻ have the earlier givensignifications (provided that the sum of carbon atoms of B¹¹ and B¹²,carbon atoms forming the crosslinkage and k does not exceed 13)]. Inparticular, as A, a group expressed by any one of formulae (a₂):

[in which R²¹ and R³¹ signify lower alkyl independently of each other;and k and X⁻ have the earlier given significations] is preferred. In themost favorable embodiments, A is a group expressed by a formula (a₃)

[in which k, R²¹, R³¹ and X⁻ have the earlier given significations] or aformula (a₄)

[in which k, R²¹, R³¹ and X⁻ have the earlier given significations].

The embodiments in which k in the formulae (a₁), (a₂), (a₃) or (a₄) iszero (0) are preferred.

Furthermore, the embodiments in which both R²¹ and R³¹ in the formulae(a₂), (a₃) or (a₄) are methyl groups are preferred.

As X⁻ in the formulae (a₁), (a₂), (a₃) or (a₄), for example, anionsformed from halogen atoms such as

Cl⁻, Br⁻,

and the like are preferred.

In the formula (b₀), R⁵ signifies hydrogen or a lower alkyl optionallyhaving substituent(s) selected from the group consisting of phenyl andcycloalkyl, and R⁷ signifies hydrogen or a lower alkyl; or either one ofR⁵ and R⁷ signifies a single bond or C₁-C₃ alkylene binding to abindable optional site on B².

Said definition of R⁵, “lower alkyl optionally having substituent(s)selected from the group consisting of phenyl and cycloalkyl”, signifiesthe same to the earlier given definition of R², R³ or R⁴, “lower alkyloptionally having substituent(s) selected from the group consisting ofphenyl and cycloalkyl”, specific examples of which also being the same.Of those named examples, methyl and ethyl are preferred.

As lower alkyl represented by R⁷, methyl and ethyl are preferred.

Where either one of R⁵ and R⁷ binds to a bindable optional site on B²,preferred R⁵ or R⁷ is single bond, methylene or ethylene.

R⁶ signifies hydrogen, lower alkyl or a group represented by —N(R⁸)R⁹.

As lower alkyl represented by R⁶, methyl, ethyl, propyl and butyl arepreferred.

R⁸ and R⁹ signify, independently of each other, hydrogen or lower alkyl.

As lower alkyl represented by R⁸ or R⁹, methyl, ethyl, and propyl arepreferred.

It is preferable that both R⁸ and R⁹ are hydrogen atoms.

Therefore, as the groups expressed as —N(R⁸)R⁹, for example, amino,methylamino, dimethylamino, ethylmethylamino and diethylamino, inparticular, amino, are preferred.

As R⁶, hydrogen and those groups expressed as —N(R⁸)R⁹ are preferred,hydrogen being the most preferred.

In preferred embodiments of R⁵, R⁶ and R⁷, R⁵ signifies a single bond ora C₁-C₃ alkylene binding to a bindable optional site on B²; R⁶ signifieshydrogen, lower alkyl or a group expressed as —N(R⁸)R⁹, preferablyhydrogen; and R⁷ signifies hydrogen.

In more specific, preferred embodiments where A in the general formula(I) is a group expressed by the formula (b₀), A is a group representedby a formula (b₁)

[in which B²¹ and B²² signify, independently of each other, a C₁-C₆saturated or unsaturated aliphatic hydrocarbon group, which may bemutually crosslinked; m signifies 0, 1 or 2; R⁷¹ signifies hydrogen orlower alkyl; and R⁶ has the earlier given signification (provided thatthe sum of carbon atoms of B²¹ and B²², carbon atoms forming thecrosslinkage and m does not exceed 13)], in particular, R⁷¹ in thatgroup is hydrogen. In still more favorable embodiments, A is a grouprepresented by any one of the formulae (b₂)

[in which m and R⁶ have the earlier given significations]. It is ofparticular advantage that A is a group represented by a formula (b₃)

[in which m and R⁶ have the earlier given significations].

In the formulae (b₁), (b₂) or (b₃), m is preferably 1 or 2.

Furthermore, in the formulae (b₁), (b₂) or (b₃), R⁶ is preferablyhydrogen.

Ar signifies aryl or heteroaryl optionally having substituent(s)selected from a group consisting of halogen, lower alkyl, lower alkenyland lower alkoxy.

“Aryl or heteroaryl optionally having substituent(s) selected from agroup consisting of halogen, lower alkyl, lower alkenyl and loweralkoxy” signify unsubstituted aryl or heteroaryl, or the aryl orheteroaryl having substituent(s) at substitutable optional position(s)thereon, said 1, 2 or more, preferably 1 or 2, substituent(s) which arethe same or different and selected from the group consisting of halogen,lower alkyl, lower alkenyl and lower alkoxy.

As the substituent halogen, for example, fluorine, chlorine and bromineare preferred.

As the substituent lower alkyl, for example, methyl, ethyl, propyl andisopropyl are preferred.

As the substituent lower alkenyl, for example, vinyl is preferred.

As the substituent lower alkoxy, for example, methoxy, ethoxy andmethylenedioxy are preferred.

As the substituent(s), halogen is preferred.

Where Ar is “aryl”, for example, phenyl is preferred.

Where Ar is “heteroaryl”, for example, 2-pyridyl, 2-thiazolyl, 2-thienyland 3-thienyl are preferred.

Accordingly, as examples of Ar, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,4-difluorophenyl,3,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,4-ethylphenyl, 2-vinylphenyl, 3-vinylphenyl, 4-vinylphenyl,4-methoxyphenyl, 4-ethoxyphenyl and 3,4-methylenedioxyphenyl can benamed. Of those, phenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl,4-bromophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-ethylphenyl,4-vinylphenyl and 3,4-methylenedioxyphenyl are preferred. In particular,where A in the general formula (I) is a group represented by the formula(a₀), 4-chlorophenyl is preferred, and where A is a group represented bythe formula (b₀), unsubstituted phenyl is preferred.

R¹ signifies a fluorine-substituted C₄-C₆ cycloalkyl optionally havinghydroxyl group(s).

“Fluorine-substituted C₄-C₆ cycloalkyl optionally having hydroxylgroup(s)” include C₄-C₆ cycloalkyl substituted with 1, 2 or more,preferably 1 or 2, inter alia, 2 fluorine atoms at substitutable,optional position(s), said cycloalkyl groups further having 1, 2 ormore, preferably 1, hydroxyl group(s) at substitutable optionalposition(s) thereon or not having them.

As “cycloalkyl” of R¹, for example, cyclopentyl is preferred.

Accordingly, examples of R¹ include 1-fluorocyclobutyl,1-fluorocyclopentyl, 2-fluorocyclobutyl, 2-fluorocyclopentyl,3-fluorocyclobutyl, 3-fluorocyclopentyl, 2,2-difluorocyclobutyl,2,2-difluorocyclopentyl, 3,3 -difluorocyclobutyl,3,3-difluorocyclopentyl, 3,3-difluoro-4-hydroxycyclopentyl,3,3,4,4-tetrafluorocyclopentyl, 2,3-difluorocyclobutyl,2,3-difluorocyclopentyl, 3,4-difluorocyclopentyl,2,2,3,3-tetrafluorocyclobutyl and 2,2,3,3 -tetrafluorocyclopentyl. Ofthose, 2-fluorocyclobutyl, 2-fluorocyclopentyl, 3-fluorocyclobutyl,3-fluorocyclopentyl, 2,2-difluorocyclobutyl, 2,2-difluorocyclopentyl,3,3-difluorocyclobutyl, 3,3-difluorocyclopentyl,3,3-difluoro-4-hydroxycyclopentyl, 3,3,4,4-tetrafluorocyclopentyl and2,2,3,3-tetrafluorocyclopentyl are convenient. In particular,3,3-difluorocyclopentyl is preferred.

In the general formula (II), A^(p) signifies a group represented by theformulae (a_(p0)) or (b_(p0))

[in which B¹, B², R⁵, R²⁰ and R⁴⁰ have the earlier givensignifications].

Needless to say, preferred embodiments of the compounds represented bythe general formula (II) correspond to the preferred embodiments of thecompounds represented by the general formula (I).

As examples of “optionally substituted lower alkyl” of R²⁰ or R⁴⁰,independently of each other, methyl, ethyl, propyl, isopropyl,cyclohexylmethyl, cycloheptylmethyl and benzyl can be named, inparticular, methyl being preferred.

As R⁴⁰, a single bond or C₁-C₃ alkylene which bind to a bindableoptional site on B¹, in particular, a single bond, methylene or ethyleneare preferred.

In more specific, preferred embodiments wherein A^(p) is a grouprepresented by the formula (a_(p0)), for example, A^(p) is a grouprepresented by a formula (a_(p1))

[in which B¹¹, B¹², k and R²⁰ have the earlier given significations], inparticular, a group represented by any one of formulae (a_(p2))

[in which k and R²⁰ have the earlier given significations]. In mostfavorable embodiments, for example, A^(p) is a group represented by aformula (a_(p3))

[in which k and R²⁰ have the earlier given significations] or a formula(a_(p4))

[in which k and R²⁰ have the earlier given significations].

In more specific, preferred embodiments wherein A^(p) is a grouprepresented by the formula (b_(p0)), for example, A^(p) is a grouprepresented by a formula (b_(p1))

[in which B²¹, B²² and m have the earlier given significations], inparticular, is a group represented by any one of formulae (b_(p2))

[in which m has the earlier given signification]. In most favorableembodiments, A^(p) is a group represented by a formula (b_(p3))

[in which m has the earlier given signification].

As Ar or R¹ in the general formula (II), examples similar to those namedfor Ar or R¹ of the general formula (I) can be named, preferred examplesagain being the same. Specific examples of B¹¹, B¹², B²¹, B²², k, m orR⁵ in the formulae (a_(p1)), (a_(p2)), (a_(p3)), (a_(p4)), (b_(p0)),(b_(p1)), (b_(p2)) or (b_(p3)) are same to those for B¹¹, B¹², B²¹, B²²,k, m or R⁵ in the formulae (a₁), (a₂), (a₃), (a₄), (b₀), (b₁), (b₂) or(b₃), preferred examples again being the same.

As “salts” of the compounds represented by the general formula (II), forexample, those acid addition salts via basic nitrogen atoms can benamed.

As said acid addition salts, for example, inorganic acid salts such ashydrochloride, sulfate, nitrate, phosphate and perchlorate; organic acidsalts such as maleate, fumarate, tartarate, citrate, asocorbate andtrifluoroacetate; and sulfonic acid salts such as methanesulfonate,isethionate, benzenesulfonate and p-toluene-sulfonate can be named.

Now production processes of the compounds to which the present inventionrelates shall be explained.

Compounds (I) of the present invention can be produced, for example, bythe following processes or those described in working examples, it beingunderstood that production processes of the compounds (I) of the presentinvention are not limited by these reaction examples.

Production Process 1

Through reaction of a compound represented by a general formula (II-1)

[in which A^(pa) signifies a group represented by the formula (a_(p0))

and Ar, B¹, R¹, R²⁰ and R⁴⁰ have the earlier given significations]or a salt thereof, with a compound represented by a general formula(III)R³⁰-L  (III)

[in which L signifies a leaving group, and R³⁰ signifies a lower alkyloptionally having substituent(s) selected from a group consisting ofphenyl and cycloalkyl], a compound represented by a general formula(I-1)

[in which R²² signifies a lower alkyl optionally having substituent(s)selected from the group consisting of phenyl and cycloalkyl; and Ar, B¹,R¹, R³⁰, R⁴⁰ and X⁻ have the earlier given significations] can beprepared.

“Salts” of the compounds represented by the general formula (II-1)signify acid addition salts via amino or imino, examples of whichinclude inorganic acid salts such as hydrochloride, sulfate, nitrate,phosphate and perchlorate; organic acid salts such as maleate, fumarate,tartarate, citrate, ascorbate and trifluoroacetate; and sulfonic acidsalts such as methanesulfonate, isethionate, benzenesulfonate andp-toluenesulfonate.

As the “leaving group” expressed as L, for example, halogen atoms suchas chlorine, bromine and iodine; alkylsulfonyloxy group such asmethylsulfonyloxy: and arylsulfonyloxy group such asp-toluenesulfonyloxy may be named.

The reaction of a compound represented by the general formula (II-1) ora salt thereof with a compound represented by the general formula (III)is normally conducted in an inert solvent having no adverse influence onthe reaction.

As such inert solvent, for example, ethers such as diethyl ether,tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene,toluene, chlorobenzene and xylene; halogenated solvents such aschloroform and dichloromethane; aprotic polar solvents such as acetoneand acetonitrile; or mixed solvents of the foregoing can be used.

The compound of the general formula (III) is normally used at the ratiosof 1 mol-molar excess, in particular, 1-10 mols, per mol of the (II-1)compound. Especially when R²⁰ in the (II-1) compound is hydrogen, atleast 2 mols of (III) compound is used.

The reaction temperature is normally in a range from about 0° C. toboiling point of the solvent, and the reaction time, from 10 minutes to48 hours, while those conditions deviating from above ranges can be usedwhere necessary.

The above reaction may be conducted in the presence of a base, forsmooth progress of the reaction.

As suitable base, for example, alkali metal bicarbonates such as sodiumhydrogencarbonate and potassium hydrogencarbonate; alkali metalcarbonates such as sodium carbonate and potassium carbonate; tertiaryaliphatic amines such as trimethylamine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such aspyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline andisoquinoline may be named.

The use rate of said base is normally in a range of 1 mol-molar excess,preferably 1-10 mols, per mol of the (II-1) compound.

After termination of the reaction, conventional treatments are conductedto provide a compound of the general formula (I-1).

Production Process 2

Through reaction of a compound of a general formula (II-2)

[in which A^(pa1) signifies a group expressed by the formula (a_(p01))

and Ar, B¹, R¹ and R⁴⁰ have the earlier given significations]or a salt thereof with a compound of a general formula (IV)L¹-R³¹-L²   (IV)

[in which L¹ and L² respectively signifies a leaving group independentlyof each other; and R³¹ signifies a C₂-C₅ alkylene which may beinterrupted with oxygen],

a compound represented by a general formula (I-2)

[in which Ar, B¹, R¹, R³¹, R⁴⁰ or X⁻ have the earlier givensignifications] can be prepared.

As examples of the “salts” of the compounds represented by the generalformula (II-2), those similar to the salts of the compounds (II-1) inthe above production process 1 can be named.

As L¹ or L² “leaving group”, same leaving groups as those expressed as Lin the above production process 1 can be named.

The reaction of a compound of the general formula (II-2) or a saltthereof with a compound of the general formula (IV) can be conducted inthe manner similar to the reaction of a compound of the general formula(II-1) or a salt thereof with a compound of the general formula (III) inthe production process 1.

After termination of the reaction, conventional treatments are conductedto provide a compound of the general formula (I-2).

Production Process 3

Through reaction of a compound of a general formula (II-3)

[in which A^(pb) signifies a group represented by the formula (b_(p0))

and Ar, B², R¹ and R⁵ have the earlier given significations]or a salt thereof with a compound of a general formula (V)

[in which L³ signifies a leaving group; R^(6p) signifies hydrogen, alower alkyl or a group expressed as —N(R^(8p))R^(9p); R^(70p) signifiesa protective group of imino, hydrogen or a lower alkyl; R^(8p) andR^(9p) signify, independently of each other, a protective group of aminoor imino, hydrogen or lower alkyl]

or a salt thereof, a compound of a general formula (VI)

[in which Ar, B², R¹, R⁵ R^(6p) and R^(70p) have the earlier givensignifications] or its salt is obtained. Upon optionally removing theprotective groups, a compound of a general formula (I-3)

[in which R⁷⁰ signifies hydrogen or a lower alkyl, and Ar, B², R¹, R⁵and R⁶ have the earlier given significations]

or a salt thereof can be produced.

As the “salts” of the compounds represented by the general formula(II-3), (V) or (VI), those similar to the named salts of compounds(II-1) in the production process 1 can be used.

As the “leaving group” expressed as L³, for example, halogen such aschlorine, bromine and iodine; lower alkoxy such as methoxy, ethoxy,butoxy, propoxy and isopropoxy; lower alkylthio such as methylthio andethylthio; 1-imidazolyl, 1-pyrazolyl, 1-benzotriazolyl and the like maybe named.

In the above reaction, when the reactant(s) contain amino or iminogroup(s) not participating in the reaction, said amino or imino group(s)are adequately protected with protective group(s), preceding thereaction, The protective groups can be removed after the reaction.

As such “protective groups of amino or imino group(s)”, for example,aralkyl such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, benzhydryl and trityl; lower alkanoyl suchas formyl, acetyl, propionyl, butyryl and pivaloyl; benzoyl;arylalkanoyl such as phenylacetyl and phenoxyacetyl; loweralkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl and tert-butoxycarbonyl; aralkyloxycarbonyl such asbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl;lower alkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl;phthaloyl; aralkylidene such as benzylidene, p-chlorobenzylidene ando-nitrobenzylidene may be named. Also as a protective group of imino on,for example, an amidino group, nitro can be named. Of those protectivegroups, in particular, acetyl, pivaloyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl and benzyloxycarbonyl groups are preferred.

The reaction of a compound of the general formula (II-3) or a saltthereof with a compound of the general formula (V) or a salt thereof isnormally conducted in an inert solvent having no adverse effect on thereaction, using 1 mol-molar excess, preferably 1-2 mols, of the compound(V) or a salt thereof, per mol of the compound (II-3) or a salt thereof.

As the inert solvent, for example, alcohols such as methanol andethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane;aromatic hydrocarbons such as benzene, toluene, chlorobenzene andxylene; aprotic polar solvents such as dimethylsulfoxide,N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide ortheir mixtures can be used.

The reaction temperature is normally in a range from −70° C. to boilingpoint of the solvent used in the reaction, preferably from −20° C. to100° C.

The reaction time normally ranges from 5 minutes to 7 days, preferablyfrom 10 minutes to 24 hours.

The reaction may be conducted in the presence of a base, for smoothprogress of the reaction.

As the base, those similar to the useful bases in the reaction of acompound (II-1) or a salt thereof with a compound (III) in theproduction process 1 may be named as examples.

The use rate of said base is normally in a range of 1 mol-molar excess,preferably 1-10 mols, per mol of the compound (V) where said compoundcontains a protective group.

On the other hand, where an unprotected compound is used as the compound(V), preferably a salt of the same compound is used. In such a case,furthermore, it is preferred that an equivalent amount to the product ofan acid be present in the reaction system and as the acid, one derivedfrom the salt of the compound (V) can be utilized. Accordingly, when acompound (II-3) is used in free form as a starting material, the bestresult can be obtained when the free compound (II-3) and a salt of acompound (V) are reacted at a ratio of substantially 1:1. Where a saltof a compound (II-3) is used, the reaction is preferably conducted inthe presence of a base of an amount suitable for neutralizing theexcessive acid in the present reaction system.

After termination of the reaction, ordinary post-treatments areconducted to provide a crude product of a compound of the generalformula (VI) or a salt thereof. Thus obtained compound (VI) or a saltthereof is optionally purified by a means known per se, and optionallysubjected to a deprotection reaction of the amino or imino group, toprovide a compound of the formula (I-3) or a salt thereof.

Method for removing protective groups differs depending on such factorsas the kind of the protective groups and stability of the objectcompound (I-3). The deprotection can be carried out using the methodsknown per se, for example, those described in Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons Co., Ltd. (1981) ormethods analogous thereto, e.g., solvolysis using an acid or a base,that is, a method in which 0.01 mole to over excess of an acid,preferably trifluoroacetic acid, formic acid, hydrochloric acid and thelike, or equimole to over excess of a base, preferably potassiumhydroxide, calcium hydroxide and the like are acted; chemical reductionusing a metal hydride complex; or catalytic reduction using apalladium-carbon catalyst, a Raney nickel catalyst or the like.

Production Process 4

Through reduction of a compound represented by a general formula (VII)

[in which A^(pb1) signifies a group represented by a formula (b_(p01))

B²³ signifies a straight chain, branched chain and/or cyclicportion-containing C₂-C₁₀ saturated or unsaturated aliphatic hydrocarbonwhich may have hydroxyl group(s) and/or be interrupted with nitrogenatom(s); R⁷¹ signifies a single bond or a C₁-C₃ alkylene; Z signifiessulfur or a group expressed as ═N—NO₂; and Ar and R¹ have the earliergiven significations] or a salt thereof, and subsequent optionalintroduction into the same compound a lower alkyl, a compoundrepresented by a general formula (I-4)

[in which Ar, B²³, R¹, R⁵, R⁶ and R⁷¹ have the earlier givensignifications] or a salt thereof can be prepared.

As the “salts” of the compounds of the general formula (VII), thosesimilar to the salts of the compounds (II-1) used in the productionprocess 1 can be named as examples.

The reducing reaction of a compound of the general formula (VII) can beconducted, for example, by the method described in JP-Hei 1(1989)-128970A or methods analogous thereto. That is, where Z stands forsulfur, the reduction can be conducted in an inert solvent, e.g.,methylene chloride, by treating the compound (VII) with Raney nickel attemperatures ranging 0° C.-40° C. Where Z is a group expressed as═N—NO₂, the reduction can be conducted by transfer hydrogenation using,for example, formic acid, hydrazine or cyclohexene as the hydrogendonor, and palladium, as the catalyst.

The lower alkyl-introducing reaction can be optionally conducted, bymethods known per se or those analogous thereto, by using, for example,alkyl iodide, dialkyl sulfate, and the like.

After termination of the reaction, conventional treatments are conductedto provide a compound represented by the general formula (I-4) or a saltthereof.

Isolation and purification of those compounds represented by the generalformulae (I-1), (I-2), (I-3) or (I-4) or their salts can be conducted byapplying customary separation means such as column chromatography usingsilica gel, adsorbent resin or the like; liquid chromatography; solventextraction, or recrystallization, reprecipitation and the like, eithersingly or in suitable combination.

Those anions which are expressed as X⁻ in the compounds represented bythe general formula (I-1) or (I-2) are convertible to different kind ofanions by methods known per se.

As such anion-converting methods, for example, a method comprisingadsorbing a compound of the general formula (I-1) or (I-2), which has acertain kind of anion, onto a column filled with a suitable carrier,treating the same with a salt of an acid capable of providing an excessof a desired anion, and thereafter eluting the formed compound havingthe desired kind of anion can be used.

Compounds represented by the general formula (I-3) or (I-4) or theirsalts can be converted from free compounds to pharmaceuticallyacceptable salts by conventional methods. The salts can also beconverted to free compounds.

Compounds represented by the general formula (I-3) or (I-4) arepreferably isolated in the form of their salts, and therefore, afterbeing isolated as a certain kind of salt, can be converted into adifferent, desired kind of salt.

As such salt-converting methods, for example, a method comprisingadsorbing a salt of a compound of the general formula (I-3) or (I-4)onto a column filled with a suitable carrier, treating the same with anexcess of a salt of a desired acid and thereafter eluting the formed,desired salt of the same compound can be used.

Compounds represented by the general formulae (II-1), (III), (II-2),(IV), (II-3), (V) or (VII) are commercially available, or they can beprepared by known methods or methods taught in literature [cf.International Publications WO 98/05641, WO 99/40070 and WO 00/31078;Angew. Chem. Int. Edit., Vol. 6, p. 566 (1967); Synth. Commun., Vol. 25,No. 8, p. 1173 (1995) and Vol. 27, No. 14, p. 2393 (1997); J. Org.Chem., Vol. 52, p. 1700 (1987) and Vol. 57, p. 2497 (1992)], methodsanalogous thereto or those described in the following Examples andReferential Examples.

[in which A^(pp) signifies a group represented by the formula (a_(p0))or (b_(p0p))

R^(p) signifies a protective group of amino or imino, or hydrogen, or alower alkyl optionally having substituent(s) selected from the groupconsisting of phenyl and cycloalkyl; and A^(p), Ar, B¹, B², R¹, R⁵, R²⁰and R⁴⁰ have the earlier given significations].

This production method is for making compounds of the general formula(II). According to this method, a compound of the general formula (II)can be prepared by causing a compound of the general formula 2 to act ona carboxylic acid of the general formula 1 or a reactive derivativethereof to form a compound of the general formula 3, and optionallyremoving the protective group in said compound 3.

Those compounds represented by the general formulae (II-1), (II-2) or(II-3) are covered by the scope of the general formula (II).

The reaction between carboxylic acid of the general formula 1 or areactive derivative thereof with a compound of the general formula 2 isnormally conducted using 1-5 moles, preferably 1-2 moles, of thecompound 2 per mole of the compound 1 or a reactive derivative thereof.

As “reactive derivatives” of the carboxylic acid represented by thegeneral formula 1, for example, mixed acid anhydrides, active esters andactive amides can be named, which can be obtained, for example, by thosemethods described in Internationl Publication WO 98/05641.

Where a carboxylic acid of formula 1 is used in the above reaction, thereaction is preferably carried out in the presence of a condensing agentsuch as carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, diphenylphosphorylazide,dipyridyldisulfide-triphenylphosphine and the like, in particular,carbonyldiimidazole.

The use rate of the condensing agent is not subject to strictlimitation, while it is normally used in a range of 1-5 moles,preferably 1-2 moles, per mole of the carboxylic acid of the generalformula 1.

The reaction is normally carried out in an inert solvent. As examples ofthe inert solvent, diethyl ether, tetrahydrofuran,N,N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene,methylene chloride, chloroform, carbon tetrachloride, dichloroethane andtrichloroethylene, or their mixtures can be named. Of these, diethylether, tetrahydrofuran, N,N-dimethylformamide and dioxane are preferred.

The reaction temperature normally ranges from −70° C. to boiling pointof the used solvent, preferably from −20° C. to 100° C.

The reaction time normally ranges from 5 minutes to 7 days, preferablyfrom 10 minutes to 24 hours.

The reaction can also be conducted in the presence of a base, for smoothprogress of the reaction.

As the useful base, for example, sodium hydride; alkali metalbicarbonates such as sodium hydrogencarbonate and potassiumhydrogencarbonate; alkali metal carbonates such as sodium carbonate andpotassium carbonate; tertiary aliphatic amines such as trimethylamine,triethylamine, N,N-diisopropylethylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such aspyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline andisoquinoline may be named. Of these, sodium hydride is preferred.

The use rate of the base can range from the catalytic amount to 5 moles,preferably the catalytic amount, per mole of the carboxylic acid of thegeneral formula 1 or its reactive derivative.

In the above reaction, when the reactant(s) contain amino or iminogroup(s) not participating in the reaction, preferably said amino orimino group(s) are suitably protected with amino- or imino-protectivegroups before the reaction, and removed after the reaction.

As the amino- or imino-protective groups, those protective groupsdescribed in above production process 3 can be used.

After termination of the reaction, ordinary treatments are conducted toprovide a crude product of a compound of the general formula 3. Thusobtained compound 3 is optionally purified by a means known per se andoptionally subjected to a deprotection reaction of the amino or iminogroup(s), to provide a compound of the general formula (II).

As the method for removing the protective group(s), those described inthe foregoing production process can be applied in the identical manner.

Compounds represented by the general formula (II) can also be preparedby the steps of producing, in the manner similar to the above productionprocess, a compound of the general formula (II) in which R⁵, R²⁰ or R⁴⁰in the group A^(p) is(are) hydrogen, and introducing into said compounda lower alkyl optionally having substituent(s) selected from the groupconsisting of phenyl and cycloalkyl.

The reaction for introducing said lower alkyl can be conducted bysubjecting the compound of the general formula (II) in which R⁵, R²⁰ orR⁴⁰ in the group A^(p) is(are) hydrogen and (a) an aldehyde or ketoneexpressed as a general formula 5,R⁴⁴═O  5

[in which R⁴⁴ signifies a lower alkylidene optionally havingsubstituent(s) selected from the group consisting of phenyl andcycloalkyl] to reducing amination reaction, or (b) after removing theprotective group(s) of said amino or imino group(s), reacting saidcompound with a compound expressed as a general formula 6,R⁴⁵-L⁴  6

[in which L⁴ signifies a leaving group, and R⁴⁵ signifies a lower alkyloptionally having substituent(s) selected from the group consisting ofphenyl and cycloalkyl] in the presence of a base, to provide a compoundwithin the scope of the general formula (II), in which R²⁰, R⁴⁰ or R⁵are, independently of each other, lower alkyl optionally havingsubstituent(s) selected from the group consisting of phenyl andcycloalkyl.

R⁴⁴ which is “a lower alkylidene optionally having substituent(s)selected from the group consisting of phenyl and cycloalkyl” signifiesthe one which can be converted to the corresponding “lower alkyloptionally having substituent(s) selected from the group consisting ofphenyl and cycloalkyl” after termination of the above reaction.

As the “leaving group” expressed as L⁴, for example, halogen such aschlorine, bromine and iodine; alkylsulfonyloxy such asmethylsulfonyloxy; and arysulfonyloxy such as p-toluenesulfonyloxy maybe named.

The reducing amination reaction with the ketone or aldehyde in abovestep (a) is normally conducted in an inert solvent not detrimental tothe reaction.

Examples of useful inert solvent include alcohols such as methanol andethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane;aromatic hydrocarbons such as benzene and toluene; and solvent mixturesthereof. In particular, methanol, ethanol, tetrahydrofuran and tolueneare preferred.

The reaction temperature can normally be in the range of from about −30°C. to about 200° C., preferably from about 0° C. to about 100° C. Alsothe reaction time can normally be in the range of from 10 minutes to 7days, preferably from 10 minutes to 24 hours.

Futhermore, the above reducing amination reaction can be conducted byusing a reducing agent such as a metal hydride complex, e.g., sodiumborohydride, sodium cyanoborohydride, lithium aluminum hydride, sodiumtriacetoxyborohydride or a mixture of sodium cyanoborohydride with zincchloride; or by catalytic reduction using a palladium-on-carboncatalyst, a Raney nickel catalyst or the like.

Where a metal hydride complex is used as the reducing agent, the userate of the reducing agent is normally in a range of 1 mole-molarexcess, preferably 1-10 moles, per mole of the starting compound.

The reaction with a compound which is expressed as the general formula 6in the step (b) is normally conducted in the presence of a base, in aninert solvent not detrimental to the reaction.

As suitable base, for example, alkali metal bicarbonates such as sodiumhydrogencarbonate and potassium hydrogencarbonate; alkali metalcarbonates such as sodium carbonate and potassium carbonate; tertiaryaliphatic amines such as trimethylamine, triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine,N-methylpiperidine, N,N-dimethylaniline,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such aspyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and 5isoquinoline may be named. In particular, N,N-diisopropylethylamine andpotassium carbonate are preferred.

The use rate of the base can normally range 1 mole-molar excess,preferably 1-10 moles, per mole of the starting compound.

As examples of the inert solvent, ethers such as diethyl ether, lotetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene,toluene, chlorobenzene and xylene; aprotic polar solvents such asdimethylsulfoxide, N,N-dimethylformamide, acetonitrile andhexamethylphosphoric acid triamide; or their mixtures can be named.

The reaction temperature can normally range from about 0° C. to boilingpoint of the solvent used, and the reaction time can range from 10minutes to 48 hours. Where necessary, however, more or less of theseranges can be used.

Introduction or removal of protective groups of amino or imino groupscan be effected by methods known per se, for example, by those methodsdescribed in the literature identified in above production processes ormethods analogous thereto.

[in which A^(pb1), Ar and R¹ have the earlier given significations].

This production process is that for producing the compounds representedby the general formula (VII). According to this production process, acompound represented by the general formula (VII) can be prepared byhaving a compound represented by the general formula 4 act on acarboxylic acid represented by the general formula 1 or a reactivederivative thereof

The reaction between a carboxylic acid of general formula 1 or areactive derivative thereof with a compound of the general formula 4 canbe carried out in the manner similar to the reaction between acarboxylic acid of general formula 1 or a reactive derivative thereofwith a compound of the general formula 2 in above production process A.

After termination of the reaction, conventional treatments are conductedto provide a compound represented by the general formula (VII).

As these compounds represented by the general formulae 1, 2, 4, 5 or 6,commercial products may be utilized, or they can be prepared by knownmethods, methods taught in literature [cf International Publication Nos.WO 98/05641, WO 99/40070 and WO 00/31078, and JP Hei 1 (1989)-128970A],or methods analogous thereto, or those described in Examples andReferential Examples in this application, in suitable combination wherenecessary.

Utility of the compounds of the present invention is demonstrated by thefollowing tests of their inhibition of binding to muscarinic receptorsand of their antagonism to various muscarinic receptors.

Tests on Inhibition of Binding to Muscarinic Receptors

The following tests were performed according to an improvement of themethod of Hargreaves, et al. (Br. J. Pharmacol. 107: 494-501, 1992). CHOcells expressing m₂ and m₃ muscarinic acetylcholine receptor (ReceptorBiology, Inc.), 0.2 nM [³H]-N-methylscopolamine (84 Ci/mmol, New EnglandNuclear Co.) and each of the compounds to be tested, were incubated in0.5 ml of 50 mM tris-HCI-10 mM MgCl₂-1 mM EDTA solution (pH 7.4) at roomtemperature (about 20-25° C.) for 120 minutes, suction filtered over aglass filter (Packard, Unifilter Plate GF/C) and washed 4 times with 1ml of ice-cold tris-HCl buffer. The filter was dried at 50° C. for anhour, then a scintillator (Packard, Microscinti 0) was added, and theradioactivity of [³H]-N-methylscopolamine adsorbed onto the filter wascounted with a microplate scintillation counter (Packard, TopCount).Receptor non-specific binding of [³H]-N-methylscopolamine was determinedby adding 1 μM N-methylscopolamine. The binding affinity of eachcompound of the present invention to muscarinic receptors is expressedas dissociation constant (Ki) calculated from the concentration oftested compound which achieves 50% inhibition (IC₅₀ value) of binding oflabeled ligand, [³H]-N-methylscopolamine, following the method of Chengand Prusoff [Biochem Pharmacol., Vol. 22, pp. 3099-3108 (1973)]

TABLE 1 Inhibition Action on Binding to Muscarinic m₂ and m₃ ReceptorsKi (nM) m₂ m₃ m₂/m₃ Compound of 29.1 0.425 68.5 Example 6 Compound of4.76 0.079 60.2 Example 54

As is clear from the results indicated in above Table 1, compounds ofthe present invention exhibited far higher binding-inhibitory activityto m₃ receptor, than that to m₂ receptor.

Test of Antagonism to Muscarinic Receptors (in vitro)

1) Test for Antagonism to M₂ Receptor in an Isolated Rat Right Atrium

These tests were performed according to a conventional method. A male SDstrain rat (weighing 300-500 g) was killed by exsanguination, and theright atrium was isolated. This preparation was isometrically suspendedin Magnus tube filled with 20 ml of Krebs Henseleit solution (gassedwith 95% O₂-5% CO₂, 32° C.) with an initial tension of 0.5 g. The heartrate was recorded with a heart rate counter. After the preparation wasequilibrated for 30 minutes, carbachol (1.7 nM-36 mM) was cumulativelyadministered in three-fold increasing doses. Thus, a decrease in heartrate was measured to obtain a dose-response curve for the controlexperiment. After the preparation was washed with fresh solution torestore the heart rate, a test compound was administered thereto. Twentyminutes later, carbachol was cumulatively administered again. Responsesto carbachol were expressed as percentages based on the heart ratebefore administration of carbachol as 100%. The antagonistic potency(K_(B) value) of the test compound was determined from the degree ofshift of the dose-response curve obtained by treatment with individualtest compound of the present invention.

2) Tests for Antagonism to the Airway M₃ Receptor in an Isolated RatTrachea

These tests were performed according to a conventional method. A male SDstrain rat (weighing 300-500 g) was killed by exsanguination, and thetrachea was isolated. Annular segments (2 mm wide) were cut out from thetrachea and cut transversely at the anterior cartilage part to make openring preparation. The preparation was suspended in a Magnus tube filledwith 5 ml of Krebs-Henseleit solution (gassed with 95% O₂-5% CO₂, 32°C.) with an initial tension of 1.0 g and a resting tension of 0.6 g. Thetension of the preparation was recorded isometrically. After beingequilibrated for an hour, the preparation was made to contract twice bytreatment with 10⁻⁴ M carbachol, and the second contraction induced bycarbachol was used as the reference contraction. After the preparationwas washed with fresh solution to be restored to the base line, avehicle or one of the test compounds was administered to anotherpreparation prepared from the same individual. Twenty minutes later,carbachol (1.7 nM-36 mM) was cumulatively administered in three-foldincreasing doses to obtain a dose-response curve. The dose-responsecurve was plotted by expressing responses as percentages based on thereference contraction of the preparation as 100%. The antagonisticpotency (K_(B) value) of the test compound was determined from thedegree of shift of the dose-response curve obtained by treatment withthe test compound.

TABLE 2 Antagonism to Muscarinic Receptors (in vitro) K_(B) (nM) Rightatrium M₂ Trachea M₃ M₂/M₃ Compound of 9.6 0.044 218 Example 6 Compoundof 10.6 0.21 50 Example 54

As is clear from the results indicated in above Table 2, the compoundsof the present invention exhibited far more powerful antagonism to thetrachea M₃ receptor than to the right atrium M₂ receptor. Therefore, thecompounds of the present invention are more selective for trachea M₃receptor.

Test for Antagonism Against Muscarinic M₃ receptor (in vivo)

1) Tests for Bronchodilation in Anesthetized Dogs (InhalationAdministration)

Bronchodilating action after administering each of the tested compoundby inhalation was evaluated by measuring the inhibitory effect on airwayresistance-increasing reaction in methacholine provocation test. In theexperiments, 12-36 months old male beagle dogs (weighing 10-15 kg) wereused, which were anesthetized with pentobarbital (30 mg/kg, i.v.) andintubated in their bronchus. After their respiration was stabilized,they were connected to Astograph (TCK-6100H, Chest Co.) and methacholineprovocation test was conducted by 3 Hz oscillation method. Methacholinewhich is an inhalation-inducing agent was diluted with physiologic saltsolution to ten concentration levels starting from 40,000 μg/ml,successively as 20,000, 10,000, 5,000, 2,500, 1,250, 625, 312.5, 156 and78 μg/ml. Using the nebulizer in the Astograph, the test animals weremade to inhale the methacholine solutions starting from that of thelowest concentration, each for one minute per solution, and changes intheir respiration resistance was continuously recorded. Theconcentration level at which the respiration resistance reached twicethe initial value was recorded as the methacholine reaction thresholdvalue. Before evaluating the tested medicines, methacholine reactionthreshold values¹⁾ of the dogs not treated with any of the testedmedicines were measured at least twice at a week or longer interval(s)to select the dogs which showed reproducible reactions.

The inhaling administration of each of the tested medicines (1 mg/ml)was carried out for 10 minutes under anesthesis with pentobarbital (30mg/kg, i.v.) using the nebulizer in the Astograph. In 5 minutes and 4hours from the inhaling administration, methacholine provocation testswere conducted to measure the methacholine reaction threshold values²⁾after administration of the tested medicines. Same measurements after 24hours were conducted after those conducted after the dogs recovered fromthe 4^(th) hour measurements.

The bronchodilator activity of the test compound (shift value) wasdetermined according to the following equation. The result was shown inTable 3.

${{Shift}\mspace{14mu}{value}} = \frac{\begin{matrix}{{methacholine}\mspace{14mu}{reaction}\mspace{14mu}{threshold}\mspace{14mu}{values}^{2)}} \\{{after}\mspace{14mu}{tested}\mspace{14mu}{medicine}\mspace{14mu}{administration}}\end{matrix}}{\begin{matrix}{{methacholine}\mspace{14mu}{reaction}\mspace{14mu}{threshold}\mspace{14mu}{values}^{1)}} \\{{without}\mspace{14mu}{treatment}\mspace{11mu}{with}\mspace{14mu}{tested}\mspace{14mu}{medicine}}\end{matrix}}$

TABLE 3 Bronchodilation Action in Dogs Shift Value 5 minutes after 4hours after 24 hours after Compound of >30 >30 5.8 Example 6 Compoundof >30 >30 3.9 Example 54

As is clear from the results shown in above Table 3, the compounds ofthe present invention exhibited powerful bronchodilation action.

As above, the compounds of formula [I] of the present invention exhibitpotent and selective antagonism to muscarinic M₃ receptors and exhibitexcellent pharmacological activity and long duration of action also whenadministered by inhalation. Hence, they can be administered to patientsorally or parenterally, preferably by inhalation, as safe pharmaceuticsexhibiting little side effects, in the treatment of, in particular, suchrespiratory diseases as chronic obstructive pulmonary diseases, chronicbronchitis, asthma, chronic airway obstruction, fibroid lung, pulmonaryemphysema and rhinitis.

In clinically applying the compounds of the present invention for thetreatment or prophylaxis of such diseases, they may be combined withpharmaceutically acceptable adjuvants in the usual manner to formulatepharmaceutical preparation forms suitable for administration. As theadjuvants, various additives conventionally used in the field ofpharmaceutics can be used. For example, gelatin, lactose, sucrose,titanium oxide, starch, crystalline cellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch,microcrystalline wax, white petrolatum, magnesium aluminatemetasilicate, anhydrous calcium phosphate, citric acid, trisodiumcitrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicicacid, talc, vegetable oil, benzyl alcohol, acacia, propylene glycol,polyalkylene glycol, cyclodextrin and hydroxypropylcyclodextrin can benamed.

As the dosage forms of pharmaceutical compositions prepared by usingthese adjuvants, solid preparations such as tablets, capsules, granules,powders and suppositories; and liquid preparations such as syrups,elixirs and injections can be named. These preparations may beformulated according to conventional techniques in the field ofpharmaceutics. Liquid preparations may be in a form which is dissolvedor suspended in water or other suitable medium prior to use. Inparticular, injections may be in the form advancedly dissolved orsuspended in physiological saline solution or a glucose solution, or inpowder form for reconstitution by dissolution or suspension inphysiological saline or a glucose solution prior to use. If desired,such injections may contain buffer agents and/or preservatives.

Also as preparations for non-oral administration such as inhalant, theymay be formulated into aerosol, inhaling powder or inhaling liquid. Theinhaling liquid can take a form to be used as dissolved or suspended inwater or other suitable medium at the application time.

In these pharmaceutical preparations, a compound of the presentinvention may be present at a ratio of from 1.0 to 100% by weight,preferably 1.0 to 60% by weight, based on the total weight of thepreparation. These pharmaceutical preparations may additionally containother therapeutically effective compounds.

When the compounds of the present invention are used as medicines, theirdosage level and dosage schedule may vary according to sex, age and bodyweight of individual patient, severity of symptoms, type and range ofthe desired therapeutic effect, and the like. Generally for oraladministration, they can be administered in a daily dose of 0.1 to 100mg/kg for an adult at one time or in several divided doses. Forparenteral administration, they can be administered in a daily dose of0.001 to 10 mg/kg for an adult, at one time or in several divided doses.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter the present invention is more specifically explained withreference to working examples, it being understood that the examples arein no way limitative of the scope of the invention.

EXAMPLE 14-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

(Step 1)

Synthesis of 1-methylpiperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a solution of 17 mg of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate and 0.03ml of formaldehyde (35% aqueous solution) in 1 ml of methanol, 0.3 ml ofadvancedly prepared 0.3 M methanol solution of sodium cyanoborohydrideand zinc chloride (1:0.5) was added at room temperature, followed by 30minutes' stirring at the same temperature. The reaction liquid wasdiluted with ethyl acetate, washed successively with a saturated sodiumhydrogencarbonate solution and with saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, 19 mg of the title compound was obtained.

(Step 2)

Synthesis of4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanolyl)oxy)-1,1-dimethylpiperidiniumbromide

To 18 mg of 1-methylpiperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 0.5ml of 10% methyl bromide-acetonitrile solution was added at roomtemperature, followed by standing for 15 hours at the same temperature.The solvent was condensed under reduced pressure, the residue obtainedwas purified with reversed phase medium pressure liquid chromatography[ODS-AQ 120-S50 (YMC Co.)] (eluent: tetrahydrofuran/water=1/1) toprovide 17 mg of the title compound as a colorless solid.

¹H-NMR (D₂O, δPPM): 1.78-2.36 (10H, m), 2.72-2.86 (1H, m), 3.02 (3H, s),3.04 (3H, s), 3.18-3.61 (4H, m), 5.04-5.17 (1H, m), 7.40-7.60 (3H, m),7.60-7.72 (2H, m)

ESI-MS (m/e, as (C₂₀H₂₈F₂NO₃)⁺): 368

EXAMPLE 24-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.The product was obtained as a colorless, oily substance.

¹H-NMR (CD₃OD, δPPM): 1.68-2.25 (10H, m), 2.32 (3H, s), 3.12 (6H, s),3.13-3.46 (5H, m), 4.97-5.08 (1H, m), 7.21 (2H, d, J=8.4 Hz), 7.49 (2H,d, J=8.4 Hz)

ESI-MS (m/e, as (C₂₁H₃₀F₂NO₃)⁺): 382

EXAMPLE 34-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)-ethanoate.The product was obtained as a colorless, oily substance.

¹H-NMR (CD₃OD, δPPM): 1.67-2.33 (10H, m), 3.14 (6H, s), 3.16-3.46 (5H,m), 5.02-5.10 (1H, m), 5.25 (1H, dd, J=1.8 Hz, 11.7 Hz), 5.80 (1H, dd,J=1.8 Hz, 17.7 Hz), 6.73 (1H, dd, J=11.7 Hz, 17.7 Hz), 7.46 (2H, d,J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz)

ESI-MS (m/e, as (C₂₂H₃₀F₂NO₃)⁺): 380

EXAMPLE 44-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)-ethanoate.The product was obtained as a colorless, oily substance.

¹H-NMR (CD₃OD, δPPM): 1.22 (3H, t, J=7.7 Hz), 1.60-2.30 (10H, m), 2.64(2H, q, J=7.7 Hz), 3.12 (6H, s), 3.09-3.43 (5H, m), 5.02-5.10 (1H, m),7.24 (2H, d, J=8.5 Hz), 7.53 (2H, d, J=8.5 Hz).

ESI-MS (m/e, as (C₂₂H₃₂F₂NO₃)⁺): 396

EXAMPLE 54-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 0.80-2.35 (10H, m), 3.05-3.20 (1H, m), 3,30 (3H,s), 3.44-3.75 (2H, m), 3.62 (3H, s), 3.95-4.30 (2H, s), 5.15-5.25 (1H,m), 7.03 (2H, t, J=8.8 Hz), 7.68 (2H, dd, J=5.4, 8.8 Hz)

ESI-MS (m/e, as (C₂₀H₂₇F₃NO₃)⁺): 386

EXAMPLE 64-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.60-2.32 (10H, m), 3.15 (3H, s), 3.18 (3H, s),3.20-3.50 (5H, m), 5.03-5.12 (1H, m), 7.39 (2H, d, J=8.4 Hz), 7.63 (2H,d, J=8.4 Hz).

ESI-MS (m/e, as (C₂₀H₂₇ClF₂NO₃)⁺): 402

EXAMPLE 74-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyl)oxy)-1,1-dimethyloiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperndin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.69-2.33 (10H, m), 3.15 (3H, s), 3.18 (3H, s),3.22-3.45 (5H, m), 5.04-5.11 (1H, m), 7.52-7.62 (4H, m).

ESI-MS (m/e, as (C₂₀H₂₇BrF₂NO₃)⁺): 446

EXAMPLE 84-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)ethanoyl)oxy)-1.1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.52-2.32 (10H, m), 3.04 (3H, s), 3.09-3.45 (5H,m), 3.13 (3H, s), 5.05-5.13 (1H, m), 7.29-7.43 (3H, m), 7.76-7.80 (1H,m)

ESI-MS (m/e, as (C₂₀H₂₇ClF₂NO₃)⁺): 402

EXAMPLE 94-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.70-2.34 (10H, m), 3.16 (3H, s), 3.17 (3H, s),3.20-3.52 (5H, m), 5.06-5.17 (1H, m), 6.93-7.09 (2H, m), 7.68-7.80 (1H,m)

ESI-MS (m/e, as (C₂₀H₂₆F₄NO₃)⁺): 404

EXAMPLE 104-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl)ethanoate. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.67-2.33 (10H, m), 2.95-3.50 (5H, m), 3.15 (3H,s), 3.18 (3H, s), 5.01-5.11 (1H, m), 5.95 (1H, q, J=1.1 Hz), 6.84 (2H,dd, J=0.8 Hz, 7.8 Hz), 7.11 (1H, d, J=7.8 Hz), 7.13 (1H, s)

ESI-MS (m/e, as (C₂₁H₂₈F₂NO₅)⁺): 412

EXAMPLE 114-((((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)methyl)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (D₂O, δPPM): 1.52-2.26 (11H, m), 2.99 (3H, s), 3.15 (3H, s),3.20-3.51 (5H, m), 4.02-4.22 (2H, m), 7.23-7.42 (3H, m), 7.58-7.68 (2H,m)

ESI-MS (m/e, as (C₂₁H₃₀F₂NO₃)⁺): 382

EXAMPLE 124-((((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoyl)oxy)methyl)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.59-2.30 (11H, m), 2.37 (3H, s), 3.03 (3H, s),3.20 (3H, s), 3.23-3.55 (5H, s), 4.15 (1H, dd, J=5.7 Hz, 10.8 Hz), 4.23(1H, dd, J=6.0 Hz, 10.8 Hz), 7.23 (2H, d, J=8.2 Hz), 7.53 (2H, d, J=8.2Hz).

ESI-MS (m/e, as (C₂₂H₃₂F₂NO₃)⁺): 396

EXAMPLE 134-((((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoyl)oxy)methyl)-1,1-dimethylpiperidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)-ethanoate.The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.21 (3H, t, J=7.5 Hz), 1.52-2.24 (11H, m), 2.62(2H, q, J=7.5 Hz), 2.90-3.49 (5H, m), 2.97 (3H, s), 3.13 (3H, s), 4.09(1H, dd, J=6.3 Hz, 11.4 Hz), 4.16 (1H, dd, J=5.7 Hz, 11.4 Hz), 7.20 (2H,d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz)

ESI-MS (m/e, as (C₂₃H₃₄F₂NO₃)⁺): 410

EXAMPLE 143-Endo-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-8,8-dimethyl-8-azoniabicyclo[3.2.1]-octanebromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using 3-endo-8-azabicyclo[3.2.1]-oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.57-2.32 (12H, m), 2.56-2.72 (2H, m), 3.06 (3H,s), 3.14 (3H, s), 3.21-3.34 (1H, m), 3.72-3.82 (2H, m), 5.06 (1H, t,J=5.9 Hz), 7.40 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz)

ESI-MS (m/e, as (C₂₂H₂₉ClF₂NO₃)⁺): 428

EXAMPLE 153-Endo-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyl)oxy)-8,8-dimethyl-8-azoniabicyclo[3.2.1]-octanebromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using 3-endo-8-azabicyclo[3.2.1]-oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.75-2.30 (12H, m), 2.57-2.72 (2H, m), 3.05 (3H,s), 3.14 (3H, s), 3.20-3,34 (1H, m), 3.72-3.80 (2H, m), 5.07 (1H, t,J=5.7 Hz), 7.55 (4H, s)

ESI-MS (m/e, as (C₂₂H₂₉BrF₂NO₃)⁺): 472,474

EXAMPLE 16(3R)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)-ethanoate.The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.65-2.30 (7H, m), 2.31 (3H, s), 2.67-2.82 (1H,m), 3.03 (3H, s), 3.19 (3H, s), 3.20-3,34 (1H, m), 3.53-3.88 (4H, m),5.44-5.53 (1H, m), 7.20 (2H, d, J=8.6 Hz), 7.46 (2H, d, J=8.6 Hz)

ESI-MS (m/e, as (C₂₀H₂₈F₂NO₃)⁺): 386

EXAMPLE 17(3R)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.52-2.36 (7H, m), 2.69-2.87 (1H, m), 3.10 (3H,s), 3.21 (3H, s), 3.04-3,37 (1H, m), 3.54-3.91 (4H, m), 5.47-5.57 (1H,br), 7.02-7.17 (2H, m), 7.57-7.69 (2H, m)

ESI-MS (m/e, as (C₁₉H₂₅F₃NO₃)⁺): 372

EXAMPLE 18(3R)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorolphenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.62-2.35 (7H, m), 2.70-2.85 (1H, m), 3.12 (3H,s), 3.18-3.28 (1H, m), 3.22 (3H, s), 3.56-3.69 (2H, m), 3.70-3.82 (1H,m), 3.84-3.93 (1H, m), 5.52 (1H, brs), 7.39 (2H, d, J=8.7 Hz), 7.61 (2H,d, J=8.7 Hz)

ESI-MS (m/e, as (C₁₉H₂₅ClF₂NO₃)⁺): 388

EXAMPLE 19(3R)-3-(((2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.64-2.35 (7H, m), 2.70-2.85 (1H, m), 3.11 (3H,s), 3.17-3.26 (1H, m), 3.21 (3H, s), 3.57-3.68 (2H, m), 3.88 (1H, dd,J=6.3 Hz, 13.8 Hz), 5.48-5.56 (1H, m), 7.54 (4H, s)

ESI-MS (m/e, as (C₁₉H₂₅BrF₂NO₃)⁺): 432,434

EXAMPLE 20(3S)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.57-2.30 (7H, m), 2.68-2.86 (1H, m), 3.11 (3H,s), 3.22 (3H, s), 3.13-3.39 (1H, m), 3.51-3.94 (4H, m), 5.47-5.67 (1H,br), 7.03-7.17 (2H, m), 7.57-7.70 (2H, m)

ESI-MS (m/e, as (C₁₉H₂₅F₃NO₃)⁺): 372

EXAMPLE 21(3S)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.62-2.30 (7H, m), 2.67-2.83 (1H, m), 3.11 (3H,s), 3.07-3.27 (1H, m), 3.22 (3H, s), 3.53-3.93 (4H, m), 5.46-5.57 (1H,m), 7.39 (2H, d, J=8.7 Hz), 7.60 (2H, d, J=8.7 Hz)

ESI-MS (m/e, as (C₁₉H₂₅ClF₂NO₃)⁺): 388

EXAMPLE 22(3S)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyl)oxy)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoate.The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.61-2.31 (7H, m), 2.70-2.85 (1H, m), 3.11 (3H,s), 3.16-3.26 (1H, m), 3.23 (3H, s), 3.56-3.89 (3H, m), 3.90 (1H, dd,J=6.3 Hz, 13.6 Hz), 5.47-5.57 (1H, m), 7.54 (4H, s)

ESI-MS (m/e, as (C₁₉H₂₅BrF₂NO₃)⁺): 432,434

EXAMPLE 234-((((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)methyl)-1,1-dimethyl-1,2,3,6-tetrahydropyridiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using 1,2,3,6-tetrahydropyridin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.58-2.45 (m, 8H), 3.06 (s, 3H), 3.07 (s, 3H),3.19-3.48 (m, 2H), 3.45 (t, J=6.3 Hz, 2H), 3.89 (brs, 2H), 4.66 (ABq,J=13.1 Hz, 1H), 4.71 (ABq, J=13.1 Hz, 1H), 5.62 (brs, 1H), 7.22-7.43 (m,3H), 7.55-7.68 (m, 2H)

ESI-MS (m/e, as (C₂₁H₂₈F₂NO₃)⁺): 380

EXAMPLE 244-(2-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)ethyl)-1,1-dimethyl-1,2,3,6-tetrahydropyridiniumbromide

The title compound was prepared by the treating procedures similar tothe method of Example 1, using 2-(1,2,3,6-tetrahydropyridin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.50-2.53 (10H, m), 2.98 (3H, s), 3.02 (3H, s),3.10-3.68 (5H, m), 4.21-4.47 (2H, m), 5.04 (1H, brs), 7.23-7.50 (3H, m),7.50-7.77 (2H, m)

ESI-MS (m/e, as (C₂₂H₃₀F₂NO₃)⁺): 394

EXAMPLE 259-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-1)phenylethanoyl)oxy-3,3-dimethyl-3-azoniabicyclo[3.3.1]nonaneiodide

(Step 1)

Synthesis of 3-methyl-3-azabicyclo[3.3.1]non-9-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using 3-azabicyclo[3.3.1]non-9-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetreatments similar to Example 1, (Step 1) were repeated. The resultingtwo kinds of diastereomers were separated with a preparative thin layerchromatography (Kieselgel™60F₂₅₄, Art5744 (Merck),chloroform/methanol=10/1), and as the low polar substance the titlecompound, which was named (9endo*)-body for expediency, and as the highpolar substance the title compound, which was named (9exo*)-body forexpediency, were obtained.

(Step 2)

Synthesis of9-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy-3,3-dimethyl-3-azoniabicyclo[3.3.1]-nonaneiodide

Each of the diastereomers of 3-methyl-3-azabicyclo[3.3.1]-non-9-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate wasdissolved in 0.5 ml of methyl iodide and heated under reflux for 12hours. Thereafter the excessive reagent was distilled off under reducedpressure. The residue was purified on a preparative thin layerchromatography (Aluminiumoxide™60F₂₅₄, Art5713 (Merck),chloroform/methanol=20/1) to provide the title compound whose(9endo**)-body was obtained from the (9endo*)-body, and (9exo**)-body,from the (9exo*)-body, both as colorless, oily substances.

(9endo**)-body

¹H-NMR (CDCl₃, δPPM): 1.21-2.37 (12H, m), 2.37-2.56 (1H, br), 2.56-2.74(1H, br), 3.17-3.33 (1H, m), 3.57-3.83 (2H, m), 3.70 (3H, s), 3.72 (3H,s), 3.92 (1H, d, J=3.3 Hz), 4.27 (1H, dd, J=9.4, 13.9 Hz), 4.35-4.50(1H, m), 5.42-5.53 (1H, m), 7.20-7.42 (3H, m), 7.50-7.66 (2H, d, J=7.0Hz)

ESI-MS (m/e, as (C₂₃H₃₂F₂NO₃)⁺): 408

(9exo**)-body

¹H-NMR (CDCl₃, δPPM): 1.41-2.43 (13H, m), 2.60-2.71 (1H, br), 3.10-3.42(2H, m), 3.31 (3H, s), 3.42-3.65 (2H, m), 3.60 (3H, s), 3.90-4.02 (1H,m), 4.54 (1H, s), 4.92-5.00 (1H, m), 7.22-7.45 (3H, m), 7.53-7.64 (2H,m)

ESI-MS (m/e, as (C₂₃H₃₂F₂NO₃)⁺): 408

EXAMPLE 263-Exo-((((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)methyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]-octanebromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 3-exo-8-azabicyclo[3.2.1]oct-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless solid.

¹H-NMR (CDCl₃, δPPM): 1.50-2.55 (15H, m), 3.10-3.40 (1H, m), 3.24 (3H,s), 3.31 (3H, s), 4.14-4.35 (4H, m), 7.20-7.42 (3H, m), 7.50-7.65 (2H,m)

ESI-MS (m/e, as (C₂₃H₃₂F₂NO₃)⁺): 408

EXAMPLE 27(3S)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)methyl)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using (3S)-pyrrolidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.60-2.41 (9H, m), 2.92-3.44 (3H, m), 3.11 (6H,s), 4.22-4.28 (2H, m), 7.27-7.45 (3H, m), 7.57-7.67 (2H, m)

ESI-MS (m/e, as (C₂₀H₂₈F₂NO₃)⁺): 368

EXAMPLE 28(3R)-3-(2-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)ethyl)-1,1-dimethylpyrrolidiniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 2-((3R)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.60-2.30 (10H, m), 2.38-2.52 (1H, m), 2.99 (3H,s), 3.13 (3H, s), 3.20-3,38 (2H, m), 3.48-3.56 (3H, m), 4.14-4.25 (2H,m), 7.28-7.42 (3H, m), 7.57-7.64 (2H, m)

ESI-MS (m/e, as (C₂₁H₃₀F₂NO₃)⁺): 382

EXAMPLE 29(3S)-3-(2-((2R)-2-((1R)-3,3-difluorocyclolpentyl)-2-hydroxy-2-phenylethanoyl)oxy)ethyl)-1,1-dimethylyrrolidiniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 2-((3S)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.60-2.30 (10H, m), 2.38-2.52 (1H, m), 3.03 (3H,s), 3.14 (3H, s), 3.20-3,38 (2H, m), 3.48-3.56 (3H, m), 4.14-4.25 (2H,m), 7.28-7.42 (3H, m), 7.57-7.64 (2H, m)

ESI-MS (m/e, as (C₂₁H₃₀F₂NO₃)⁺): 382

EXAMPLE 30(3aR,6aS)-5-endo-5-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-2,2-dimethyloctahydrocyclopenta(c)-pyrroliumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using (3aR,6aS)-octahydrocyclopenta(c)pyrrol-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.50-2.20 (12H, m), 2.68 (1H, t, J=10.6 Hz), 2.98(3H, s), 3.02 (3H, s), 3.03-3.45 (3H, m), 3.46-3.58 (1H, m), 5.41 (1H,t, J=4.5 Hz), 7.30-7.49 (3H, m), 7.49-7.62 (2H, m)

ESI-MS (m/e, as (C₂₂H₃₀F₂NO₃)⁺): 394

EXAMPLE 312,4-Cis-4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-1,1-dimethyl-2-vinylpiperidiniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 2,4-cis-2-vinylpiperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.53-1.71 (1H, m), 1.79-2.29 (9H, m), 3.05 (3H,s), 3.10 (3H, s), 3.14-3,34 (1H, m), 3.46-3.70 (2H, m), 4.06-4.19 (1H,m), 4.99-5.12 (1H, m), 5.59-5.70 (2H, m), 5.83-6.00 (1H, m), 7.22-7.41(3H, m), 7.56-7.66 (2H, m)

ESI-MS (m/e, as (C₂₂H₃₀F₂NO₃)⁺): 394

EXAMPLE 322-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)ethyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 2-aminoethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.60-2.30 (6H, m), 3.03 (9H, s), 3.18-3.49 (1H,m), 3.60-3.80 (2H, m), 4.50-4.70 (2H, m), 7.22-7.50 (3H, m), 7.55-7.68(2H, m)

ESI-MS (m/e, as (C₁₈H₂₆F₂NO₃)⁺): 342

EXAMPLE 333-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)propyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 3-aminopropyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CDCl₃, δPPM): 1.50-2.38 (8H, m), 3.08-3,35 (1H, m), 3.23 (9H,s), 3.55-3.82 (2H, m), 4.10-4.24 (1H, m), 4.30-4.45 (1H, m), 4.82 (1H,brs), 7.22-7.42 (3H, m), 7.58-7.70 (2H, m)

ESI-MS (m/e, as (C₁₉H₂₈F₂NO₃)⁺): 356

EXAMPLE 341,3-Trans-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)cyclobutyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 1,3-trans-3-aminocyclobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.54-1.71 (1H, m), 1.80-2.29 (5H, m), 2.32-2.52(2H, m), 2.81-3.00 (2H, m), 3.07 (9H, s), 3.19-3.40 (1H, m), 4.28-4.41(1H, m), 5.06-5.16 (1H, m), 7.23-7.41 (3H, m), 7.58-7.66 (2H, m)

ESI-MS (m/e, as (C₂₀H₂₈F₂NO₃)⁺): 368

EXAMPLE 351,3-Cis-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)cyclobutyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using 1,3-cis-3-aminocyclobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.54-2.24 (6H, m), 2.32-2.54 (2H, m), 2.72-2.90(2H, m), 3.04 (9H, s), 3.12-3.35 (1H, m), 3.78-4.00 (1H, m), 4.72-4.92(1H, m), 7.24-7.45 (3H, m), 7.56-7.68 (2H, m)

ESI-MS (m/e, as (C₂₀H₂₈F₂NO₃)⁺): 368

EXAMPLE 36(1S,4S)-4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-2-cyclopentenyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using (1S,4S)-4-amino-2-cyclopentenyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.52-2.28 (7H, m), 2.63-2.78 (1H, m), 3.07 (9H,s), 3.08-3,30 (1H, m), 4.75-4.92 (1H, m), 5.82-5.91 (1H, m), 6.30-6.50(2H, m), 7.22-7.40 (3H, m), 7.52-7.62 (2H, m)

ESI-MS (m/e, as (C₂₁H₂₈F₂NO₃)⁺): 380

EXAMPLE 37(1R,3R)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)cyclopentyltrimethylammoniumbromide

The title compound was prepared by the procedures similar to the methodof Example 1, using (1S,3S)-3-aminocyclopentyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate. Theproduct was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.55-2.30 (12H, m), 3.07 (9H, s), 3.18-3.35 (1H,m), 3.91-4.09 (1H, m), 5.25-5.33 (1H, m), 7.25-7.42 (3H, m), 7.54-7.66(2H, m)

ESI-MS (m/e, as (C₂₁H₃₀F₂NO₃)⁺): 382

EXAMPLE 384-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-1,1-diethylpiperidiniumiodide

(Step 1)

Synthesis of 1-ethylpiperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

To a solution of 25 mg of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoatein 1 ml of methanol, 50 mg of acetaldehyde and 10 mg of sodiumcyanoborohydride were added at room temperature, followed by two hours'stirring at the same temperature. The reaction liquid was diluted withchloroform, washed successively with saturated sodium hydrogencarbonatesolution and with saturated brine, and dried over anhydrous sodiumsulfate. Distilling the solvent off under reduced pressure, the residuewas purified on preparative thin layer chromatography (Kieselgel™60F₂₅₄,Art5744 (Merck), chloroform/methanol=10/1) to provide the titlecompound.

(Step 2)

Synthesis of4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-1,1-diethylpiperidiniumiodide

A solution formed by dissolving 1-ethylpiperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoatein 1 ml of ethyl iodide at room temperature was stirred for 12 hours at70° C. Excessive reagent was distilled off under reduced pressure, andthe residue was purified on preparative thin layer chromatography(Aluminiumoxide™60F₂₅₄, Art5713 (Merck), chloroform/methanol=3/1) toprovide 14 mg of the title compound as a colorless solid.

¹H-NMR (CD₃OD, δPPM): 1.23-1.34 (6H, m), 1.50-2.30 (10H, m), 3.09-3.57(9H, m), 5.04-5.12 (1H, m), 7.30-7.43 (2H, m), 7.57-7.67 (2H, m)

ESI-MS (m/e, as (C₂₂H₃₁ClF₂NO₃)⁺): 430

EXAMPLE 391-Cycloheptylmethyl-4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-1-methylpiperidiniumiodide

(Step 1)

Synthesis of 1-(cycloheptylmethyl)piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a solution of 9.3 mg of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 1 mlof methanol, 10 mg of cycloheptanecarbaldehyde and then 0.5 ml ofadvancedly prepared 0.3 M methanol solution of sodium cyanoborohydrideand zinc chloride (1:0.5) were added at room temperature, followed by 30minutes' stirring at the same temperature. The reaction liquid wasdiluted with ethyl acetate, washed successively with saturated sodiumhydrogenecarbonate solution and with saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, the residue was purified on preparative thin layerchromatography (Kieselgel™60F₂₅₄, Art5744 (Merck),chloroform/methanol=10/1) to provide the title compound.

(Step 2)

Synthesis of1-cycloheptylmethyl-4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-1-methylpiperidiniumiodide

A solution formed by dissolving 1-(cycloheptyl-methyl)piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 0.3ml of methyl iodide at room temperature was allowed to stand for 12hours at the same temperature, and excessive reagent was distilled offunder reduced pressure. The diastereomers in the residue were separatedon preparative thin layer chromatography (kieselgel™60F₂₅₄, Art5744(Merck), chloroform/methanol=5/1) to provide the title compoundrespectively as 3.8 mg (low polar substance) and 2.8 mg (high polarsubstance) of colorless oily substances.

(Low Polar Substance)

¹H-NMR (CD₃OD, δPPM): 0,75-2.31 (23H, m), 2.98-3.67 (7H, m), 3.09 (3H,s), 4.52-5.01 (1H, m), 7.25-7.45 (3H, m), 7.59-7.69 (2H, m)

ESI-MS (m/e, as (C₂₇H₄₀F₂NO₃)⁺): 464

(High Polar Substance)

¹H-NMR (CD₃OD, δPPM): 1.00-2.35 (23H, m), 2.95-3.43 (7H, m), 3.06(3Hx6/7, s), 3.08 (3Hx1/7, s), 5.00-5.10 (1H, m), 7.30-7.48 (3H, m),7.57-7.68 (2H, m)

ESI-MS (m/e, as (C₂₇H₄₀F₂NO₃)⁺): 464

EXAMPLE 40(3R)-1-cycloheptylmethyl-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-1-methylpyrrolidiniumbromide

Using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, twodiastereomers of the title compound were prepared through the treatmentssimilar to those in the method of Example 39, both as colorless oilysubstances.

(Low Polar Substance)

¹H-NMR (CD₃OD, δPPM): 1.10-2.30 (21H, m), 2.80-3.03 (1H, m), 3.03 (3H,s), 3.03-3.22 (1H, m), 3.48-3.62 (2H, m), 3.73-3.86 (1H, m), 3.95-4.10(2H, m), 4.28-4.40 (1H, m), 5.02-5.65 (1H, m), 7.22-7.40 (3H, m),7.50-7.60 (2H, m)

ESI-MS (m/e, as (C₂₆H₃₈F₂NO₃)⁺): 450

(High Polar Substance)

¹H-NMR (CD₃OD, δPPM): 1.18-2.30 (21H, m), 2.88-3.08 (1H, m), 3.38 (3H,s), 3.08-3.42 (2H, m), 3.70-3.92 (2H, m), 4.00-4.15 (1H, m), 4.41-4.60(1H, m), 5.01-5.14 (1H, m), 7.21-7.40 (3H, m), 7.50-7.60 (2H, m)

ESI-MS (m/e, as (C₂₆H₃₈F₂NO₃)⁺): 450

EXAMPLE 413-Endo-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-8-isopropyl-8-methyl-azoniabicyclo[3.2.1]octanebromide

(Step 1)

Synthesis of 3-endo-8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a solution of 2.13 g of 3-endo-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 50ml of methanol, 1 ml of acetone, and then 30 ml of advancedly prepared0.3 M methanol solution of sodium cyanoborohydride and zinc chloride(1:0.5) were added at room temperature, followed by 3 days stirring atthe same temperature. The reaction liquid was diluted with ethylacetate, washed successively with saturated sodium hydrogenecarbonatesolution and with saturated brine, and dried over anhydrous sodiumsulfate. Distilling the solvent off under reduced pressure, the residuewas purified on preparative thin layer chromatography (kieselgel™60F₂₅₄,Art5744 (Merck), chloroform/methanol=10/1) to provide 2.25 g of thetitle compound.

(Step 2)

Synthesis of3-endo-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-8-isopropyl-8-methyl-azoniabicyclo-[3.2.1]octanebromide

To 2.25 g of 3-endo-8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 10 mlof 10% methyl bromide-acetonitrile solution was added at roomtemperature, followed by 15 hours' standing at the same temperature.Recovering the precipitated solid by filtration, 963 mg of the titlecompound was prepared as colorless crystals.

¹H-NMR (CD₃OD, δPPM): 1.34 (3H, d, J=6.3 Hz), 1.35 (3H, d, J=6.3 Hz),1.67-2.28 (12H, m), 2.50-2.73 (2H, m), 2.81 (3H, s), 3.21-3.42 (1H, m),3.80-3.98 (2H, m), 4.00-4.19 (1H, m), 5.05-5.19 (1H, m), 7.28-7.50 (3H,m), 7.55-7.68 (2H, m)

ESI-MS (m/e, as (C₂₄H₃₄F₂NO₃)⁺): 422

EXAMPLE 42 3-Endo-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(24-difluorophenyl)ethanoyl)oxy)-8-isopropyl-8-methyl-azoniabicyclo-[3.2.1]octanebromide

Using 3-endo-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 41. The product was obtained as colorless crystals.

¹H-NMR (CD₃OD, δPPM): 1.36 (6H, d, J=6.3 Hz), 1.70-2.30 (12H, m),2.54-2.74 (2H, m), 2.82 (3H, s), 3.12-3,35 (1H, m), 3.84-3.98 (2H, m),4.01-4.20 (1H, m), 5.10-5.21 (1H, m), 6.92-7.10 (2H, m), 7.68-7.80 (1H,m)

ESI-MS (m/e, as (C₂₄H₃₂F₄NO₃)⁺): 458

EXAMPLE 433-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)propyl(benzyl)dimethylammoniumbromide

Using 3-(benzylamino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 1. The product was obtained as colorless oily substance.

¹H-NMR (CDCl₃, δPPM): 1.52-2.30 (8H, m), 2.98-3.22 (1H, m), 3.08 (3H,s), 3.09 (3H, s), 3.60-3.90 (2H, m), 4.09-4.22 (1H, m), 4.28-4.41 (1H,m), 4.84 (2H, s), 7.18-7.65 (10H, m)

ESI-MS (m/e, as (C₂₅H₃₂F₂NO₃)⁺): 432

EXAMPLE 444-(((2R)-2-((1R,3R)-3-fluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoyl)oxy)-1,1-dimethylpiperidiniumbromide

Using piperidin-4-yl(2R)-2-(4-chlorophenyl)-2-((1R)-3-fluorocyclopentyl)-2-hydroxyethanoate,the title compound was prepared through the treatments as in the methodof Example 1. The product was obtained as colorless solid.

1H-NMR (CD₃OD, δPPM): 1.45-2.10 (8H, m), 2.10-2.35 (2H, m), 3.06-3.49(5H, m), 3.15 (3H, s), 3.19 (3H, s), 4.70-5.18 (2H, m), 7.38 (2H, d,J=8.6 Hz), 7.65 (2H, d, J=8.6 Hz)

ESI-MS (m/e, as (C₂₀H₂₈ClFNO₃)⁺): 384

EXAMPLE 45(2R)-2-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-8-oxa-5-azoniaspiro[4.5]decanechloride

To an acetonitrile solution containing 11 mg of (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 30 mgof 1-chloro-2-(2-chloroethoxy)ethane was added at room temperature,followed by 12 hours' heating under reflux. Distilling the solvent offunder reduced pressure, the residue was purified on preparative thinlayer chromatography (Aluminiumoxide™60F₂₅₄, Art5713 (Merck),chloroform/methanol=10/1) to provide 2.8 mg of the title compound as acolorless oily substance.

¹H-NMR (CD₃OD, δPPM): 1.50-2.80 (8H, m), 3.00-4.03 (13H, m), 5.45-5.60(1H, m), 7.24-7.70 (5H, m)

ESI-MS (m/e, as (C₂₁H₂₈F₂NO₄)⁺): 396

EXAMPLE 46(2R)-2-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-5-azoniaspiro[4.5]decanebromide

Using 1,5-dibromopentane, the title compound was prepared through thetreatments as in the method of Example 45. The product was obtained as acolorless oily substance.

¹H-NMR (CDCl₃, δPPM): 1.48-2.40 (13H, m), 2.83-3,35 (4H, m), 3.66-4.40(6H. m), 5.50-5.68 (1H, m), 7.20-7.41 (3H, m), 7.48-7.65 (2H, m)

ESI-MS (m/e, as (C₂₂H₃₀F₂NO₃)⁺): 394

EXAMPLE 47(2R)-2-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyl)oxy)-5-azoniaspiro[4.4]nonanebromide

Using 1,4-dibromobutane, the title compound was prepared through thetreatments as in the method of Example 45. The product was obtained as acolorless oily substance.

¹H-NMR (CDCl₃, δPPM): 1.50-2.40 (11H, m), 2.75-2.94 (1H, m), 3.10-3.25(1H, m), 3.35-4.03 (7H, m), 4.32-4.45 (1H, m), 4.75-5.05 (1H, m),5.50-5.62 (1H, m), 7.22-7.40 (3H, m), 7.50-7.64 (2H, m)

ESI-MS (m/e, as (C₂₁H₂₈F₂NO₃)⁺): 380

EXAMPLE 48 1-(Iminomethyl)piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoatemonohydrochloride

To a solution of 13 mg of piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoatein 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloridewas added, followed by 13 hours' stirring at room temperature. Thereaction liquid was condensed to dry solid. Purifying the crude producton silica gel column chromatography (eluent: chloroform/methanol=10/1),9 mg of the title compound was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.63-2.25 (10H, m), 3.20-3.77 (5H, m), 5.09-5.17(1H, m), 7.49-7.60 (4H, m), 7.86 (1H, s)

ESI-MS (m/e, as (C₁₉H₂₃BrF₂N₂O₃)⁺): 445,447

EXAMPLE 49 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.05-2.27 (11H, m), 3.00-3.45 (3H, m), 3.66-3.82(1H, m), 3.89-4.18 (3H, m), 7.21-7.44 (3H, m), 7.53-7.64 (2H, m), 7.81(1H, s)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 50 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.16-1.42 (2H, m), 1,22 (3H, t, J=7.5 Hz),1.66-2.2 (9H, m), 2.63 (2H, q, J=7.5 Hz), 3.002-3.44 (3H, m), 3.73-3.83(1H, m), 3.89-4.14 (3H, m), 7.19 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4Hz), 7.83 (1H, s)

ESI-MS (m/e, as (C₂₂H₃₀F₂N₂O₃+H)⁺): 409

EXAMPLE 51 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.16-1.42 (2H, m), 1,22 (3H, t, J=7.5 Hz),1.66-2.2 (9H, m), 2.63 (2H, q, J=7.5 Hz), 3.002-3.44 (3H, m), 3.73-3.83(1H, m), 3.89-4.14 (3H, m), 7.19 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4Hz), 7.83 (1H, s)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 409

EXAMPLE 52 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-ethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 0.80-2.22 (11H, m), 2.89-3.49 (3H, m), 3.70-4.17(4H, m), 7.36 (2H, d, J=8.6 Hz), 7.60 (2H, d, J=8.6 Hz), 7.84 (1H, s)

ESI-MS (m/e, as (C₂₀H₂₅ClF₂N₂O₃+H)⁺): 415

EXAMPLE 53 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.18-1.43 (2H, m), 1.62-2.25 (9H, m), 3.03-3.46(3H, m), 3.74-3.84 (1H, m), 3.92-4.14 (3H, m), 7.47-7.62 (4H, m), 7.83(1H, s)

ESI-MS (m/e, as (C₂₀H₂₅BrF₂N₂O₃+H)⁺): 459,461

EXAMPLE 54-1 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-(piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.00-2.25 (13H, m), 2.82-3.02 (1H, m), 3.10-3.40(2H, m), 3.65-3.80 (1H, m), 3.85-4.00 (1H, m), 4.10-4.30 (2H, m),7.25-7.45 (3H, m), 7.58-7.70 (2H, m), 7.80 (1H, s)

ESI-MS (m/e, as (C₂₁H₂₈F₂N₂O₃+H)⁺): 395

EXAMPLE 54-2 Salt Exchange 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrobromide

A solution of 50 mg of 2-(1-(iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride in 2 ml of ultrapure water was developed on reversedphase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC Co.)],and 60 ml of 0.2 M aqueous sodium bromide solution was flowed. Afterwashing with 100 ml of ultrapure water, the title compound was elutedfrom tetrahydrofuran/water=1/5, and 35 mg thereof was obtained as acolorless solid upon condensation to dry solid.

EXAMPLE 54-3 Salt Exchange 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonophosphate

A solution of 7.0 g of 2-(1-(iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride in 50 ml of ultrapure water was developed on reversedphase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC Co.)],and 300 ml of 1.0 M aqueous sodium dihydrogenephosphate solution, 300 mlof 0.2 M phosphoric acid and 300 ml of ultrapure water were flowed bythe order stated, followed by elution with tetrahydrofuran/water=1/9.Distilling the solvent off under reduced pressure, the residue wascrystallized in ethanol and recovered by filtration, to provide 6.5 g ofthe title compound as a colorless solid.

EXAMPLE 54-4 Salt Exchange 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclonentyl)-2-hydroxy-2-phenylethanoatefumarate

A solution of 75 mg g of 2-(1-(iminomethyl)piperidin-4-yl)-ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride in 2 ml of ultrapure water was developed on reversedphase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC Co.)],and 60 ml of 0.2 M aqueous sodium monofumarate solution, 60 ml ofaqueous fumaric acid solution and 100 ml of ultrapure water were flowedby the order stated. The title compound was eluted fromtetrahydrofuran/water=1/4. Condensing the same to dry solid, 41 mg of acolorless solid was obtained.

EXAMPLE 55 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate monohydrochloride

Using 2-(piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.10-2.23 (13H, m), 2.89-3.30 (3H, m), 3.70-3.80(1H, m), 3.90-4.00 (1H, m), 4.16-4.30 (2H, m), 7.35-7.40 (2H, m),7.58-7.63 (2H, m), 7.81 (1H, brs)

ESI-MS (m/e, as (C₂₁H₂₇ClF₂N₂O₃+H)⁺): 429

EXAMPLE 56 2-(1-(Iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)-ethanoatemonohydrochloride

Using 2-(piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate,the title compound was prepared through the treatments as in the methodof Example 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.12-2.24 (13H, m), 2.90-3.03 (1H, m), 3.16-3.28(2H, m), 3.70-3.81 (1H, m), 3.90-4.01 (1H, m), 4.16-4.30 (2H, m), 7.54(4H, brs), 7.81 (1H, s)

ESI-MS (m/e, as (C₂₁H₂₇BrF₂N₂O₃+H)⁺): 473,475

EXAMPLE 57 3-(1-(Iminomethyl)piperidin-4-yl)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 3-(piperidin-4-yl)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenyl ethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 0.85-2.30 (15H, m), 2.99-3.44 (3H, m), 3.71-4.01(2H, m), 4.16 (2H, t, J=6.3 Hz), 7.23-7.65 (5H, m), 7.83 (1H, s)

ESI-MS (m/e, as (C₂₂H₃₀F₂N₂O₃+H)⁺): 409

EXAMPLE 58 (1-Iminomethyl-1,2,3,6-tetrahydropyridin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 1,2,3,6-tetrahydropyridin-4-yl-methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.50-2.26 (8H, m), 3.15-3.39 (1H, m), 3.64 (2H, t,J=6.0 Hz), 3.95 (2Hx5/7, brs), 4.12 (2Hx2/7, brs), 4.54-4.71 (2H, m),5.65 (1Hx5/7, brs), 5.68-5.73 (1Hx2/7, m), 7.23-7.47 (3H, m), 7.54-7.73(2H, m), 7.59 (1Hx5/7, s), 7.97 (1Hx2/7, s)

ESI-MS (m/e, as (C₂₀H₂₄F₂N₂O₃+H)⁺): 379

EXAMPLE 59 (4-Hydroxy-1-(iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using (4-hydroxypiperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.10-2.30 (10H, m), 3.00-3.50 (3H, m), 3.50-3.3.90(3H, m), 3.90-4.11 (2H, m), 7.23-7.46 (3H, m), 7.58-7.76 (2H, m), 7.85(1H, d, J=4.6 Hz)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₄+H)⁺): 397

EXAMPLE 60 (1R)-1-(1-(iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using (1R)-1-(piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 0.80-1.40 (6H, m), 1.54-2.30 (10H, m), 2.90-3.15(1H, m), 3.60-4.02 (2H, m), 4.70-5.05 (1H, m), 7.22-7.46 (3H, m),7.50-7.70 (2H, m), 7.72-7.85 (1H, m)

ESI-MS (m/e, as (C₂₁H₂₈F₂N₂O₃+H)⁺): 395

EXAMPLE 61 2-(1-(iminomethyl)-4-piperidinilidene)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-(4-piperidinilidene)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.50-2.53 (12H, m), 3.00-3.65 (5H, m), 4.62-4.77(2H, m), 5.49-5.60 (1H, m), 7.22-7.42 (3H, m), 7.54-7.66 (2H, m), 7.92(1H, d, J=5.5 Hz)

ESI-MS (m/e, as (C₂₁H₂₆F₂N₂O₃+H)⁺): 393

EXAMPLE 62 2-(1-Iminomethyl-1,2,3,6-tetrahydropiridin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-(1,2,3,6-tetrahydropiridin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.52-2.48 (10H, m), 3.10-3.29 (1H, m), 3.46-3.92(4H, m), 4.19-4.40 (2H, m), 5.20 (1H, brs), 7.23-7.42 (3H, m), 7.54-7.64(2H, m), 7.85-8.00 (1H, m)

ESI-MS (m/e, as (C₂₁H₂₆F₂N₂O₃+H)⁺): 393

EXAMPLE 63 2-(4-(Iminomethyl)piperadino)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-piperadinoethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.54-2.30 (6H, m), 2.38-2.60 (4H, m), 2.65 (2H, t,J=6.0 Hz), 3.14-3.50 (5H, m), 4.20-4.42 (2H, m), 7.22-7.42 (3H, m),7.58-7.70 (2H, m) 7.83 (1H, s)

ESI-MS (m/e, as (C₂₀H₂₇F₂N₃O₃+H)⁺): 396

EXAMPLE 64 ((3R)-1-(iminomethyl)piperidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using (3R)-piperidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD3OD, δppm): 1.20-2.28 (11H, m), 2.80-3.38 (3H, m), 3.60-3.80(1H, m), 3.80-4.24 (3H, m), 7.24-7.45 (3H, m), 7.55-7.65 (2H, m),7.65-7.94 (1H, m)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 65 2-((3S)-1-(iminomethyl)piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-((3S)-piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 0.80-2.25 (13H, m), 2.70-3.12 (2H, m), 3.18-3.40(1H, m), 3.50-3.92 (2H, m), 4.13-4.35 (2H, m), 7.22-7.40 (3H, m),7.54-7.90 (3H, m)

ESI-MS (m/e, as (C₂₁H₂₈F₂N₂O₃+H)⁺): 395

EXAMPLE 66 2-((3R)-1-(iminomethyl)piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-((3R)-piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.10-2.25 (13H, m), 2.70-3.12 (2H, m), 3.18-3.40(1H, m), 3.51-3.90 (2H, m), 4.15-4.32 (2H, m), 7.22-7.40 (3H, m),7.56-7.90 (3H, m)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 67 (3S)-1-(iminomethyl)pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.05-2.27 (11H, m), 3.00-3.45 (3H, m), 3.66-3.82(1H, m), 3.89-4.18 (3H, m), 7.21-7.44 (3H, m), 7.53-7.64 (2H, m), 7.81(1H, s)

ESI-MS (m/e, as (C₂₁H₂₈F₂N₂O₃+H)⁺): 395

EXAMPLE 68 (3R)-1-(iminomethyl)pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-22-phenylethanoatemonohydrochloride

Using (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hyroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.58-2.43 (8H, m), 3.15-3.96 (5H, m), 5.35-5.55(1H, m), 7.24-7.42 (3H, m), 7.55-7.62 (2H, m), 7.93, 8.06 (1H, 2*s)

ESI-MS (m/e, as (C₁₈H₂₃F₂N₂O₃+H)⁺): 353

EXAMPLE 69 ((3R)-1-(iminomethyl)pyrrolidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using ((3R)-pyrrolidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.50-2.26 (8H, m), 2.57-2.84 (1H, m), 3.01-3.85(5H, m), 4.08-4.36 (2H, m), 7.24-7.40 (3H, m), 7.56-7.63 (2H, m),7.92-8.03 (1H, m)

ESI-MS (m/e, as (C₁₉H₂₅F₂N₂O₃+H)⁺): 367

EXAMPLE 70 ((3S)-1-(iminomethyl)pyrrolidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopenthyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using ((3S)-pyrrolidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.59-2.28 (8H, m), 2.62-2.86 (1H, m), 3.08-3.90(5H, m), 4.13-4.35 (2H, m), 7.26-7.45 (3H, m), 7.57-7.66 (2H, m),7.93-8.07 (1H, m)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 367

EXAMPLE 71 2-((3S)-1-(iminomethyl)pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-((3S)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.50-2.27 (11H, m), 2.89-3,30 (3H, m), 3.40-3.83(2H, m), 4.17-4.25 (2H, m), 7.25-7.40 (3H, m), 7.57-7.66 (2H, m), 7.92,7.98 (1H, 2*s)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 72 2-((3R)-1-(iminomethyl)pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-((3R)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.50-2.28 (11H, m), 2.88-3.84 (5H, m), 4.13-4.28(2H, m), 7.24-7.41 (3H, m), 7.57-7.64 (2H, m), 7.88, 7.97 (1H, 2*s)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 73 ((2R)-1-(iminomethyl)pyrrolidin-2-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using ((2R)-pyrrolidin-2-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.57-2.23 (10H, m), 3.14-3.43 (3H, m), 4.15-4.26(2H, m), 4.31-4.39 (1H, m), 7.28-7.42 (3H, m), 7.54-7.59 (2H, m), 7.93(1H, s)

ESI-MS (m/e, as (C₁₉H₂₅F₂N₂O₃+H)⁺): 367

EXAMPLE 74 1-(Iminomethyl)azetidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using azetidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.55-2.25 (6H, m), 3.17-3.29 (1H, m), 4.10-4.20(1H, m), 4.33-4.40 (1H, m), 4.55-4.65 (1H, m), 4.72-4.81 (1H, m),5.32-5.40 (1H, m), 7.26-7.41 (3H, m), 7.58-7.64 (2H, m), 7.89 (1H, s)

ESI-MS (m/e, as (C₁₇H₂₀F₂N₂O₃+H)⁺): 339

EXAMPLE 75 (1-(Iminomethyl)azetidin-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using azetidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.¹H-NMR (CD₃OD, δppm): 1.60-2.26 (6H, m), 3.10-3,36 (2H, m), 3.77-3.96(1H, m), 3.99-4.16 (1H, m), 4.17-4.48 (4H, m), 7.25-7.43 (3H, m),7.55-7.66 (2H, m), 7.69,7.72 (1H, 2*s)

ESI-MS (m/e, as (C₁₈H₂₃F₂N₂O₃+H)⁺): 353

EXAMPLE 76 2-(1-(Iminomethyl)azetidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclonentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 2-(azetidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.55-2.25 (8H, m), 2.71-2.87 (1H, m), 3.14-3,30(1H, m), 3.84-3.92 (1H, m), 3.97-4.07 (1H, m), 4.13-4.28 (3H, m),4.32-4.42 (1H, m), 7.26-7.39 (3H, m), 7.56-7.63 (2H, m), 7.74 (1H, brs)

ESI-MS (m/e, as (C₁₉H₂₄F₂N₂O₃+H)⁺): 367

EXAMPLE 77 (3aR,6aS)-2-(iminomethyl)octahydrocyclopenta(c)pyrrol-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using (3aR,6aS)-octahydrocyclopenta(c)pyrrol-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.50-2.40 (10H, m), 2.78-3.40 (5H, m), 3.58-3.73(1H, m), 3.79-3.90 (1H, m), 5.16-5.38 (1H, m), 7.24-7.40 (3H, m),7.50-7.63 (2H, m), 7.80 (1H, d, J=18.9 Hz)

ESI-MS (m/e, as (C₂₁H₂₆F₂N₂O₃+H)⁺): 393

EXAMPLE 78 1,3-Trans-3-((iminomethyl)amino)cyclobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 1,3-trans-3-aminocyclobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.51-2.22 (6H, m), 2.35-2.62 (4H, m), 3.10-3.40(1H, m), 4.13-4.35 (1H, m), 5.00-5.21 (1H, m), 7.20-7.40 (3H, m),7.50-7.65 (2H, m), 7.70-7.88 (1H, m)

ESI-MS (m/e, as (C₁₈H₂₂F₂N₂O₃+H)⁺): 353

EXAMPLE 79 1,4-Trans-4-((iminomethyl)amino)cyclohexyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 1,4-trans-4-aminocyclohexyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.00-2.28 (m, 15H), 3.00-3.70 (m, 3H), 4.66-5.07(m, 1H), 7.22-7.43 (m, 3H), 7.55-7.68 (m, 2H), 7.74 (d, J=0.8 Hz,1Hx7/10), 7.92 (s, 1Hx1/7), 8.02 (s, 1Hx2/10)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 80 1,4-Cis-4-((iminomethyl)amino)cyclohexyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 1,4-cis-4-aminocyclohexyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.21-2.36 (15H, m), 3.20-3.40 (1H, m), 3.40-3.70(1H, br), 5.01 (1H, brs), 7.23-7.48 (3H, m), 7.50-7.60 (2H, m),7.60-8.36 (1H, m)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₃+H)⁺): 381

EXAMPLE 81 3-((Iminomethyl)amino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 3-aminopropyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.50-2.26 (8H, m), 3.10-3.42 (3H, m), 4.23 (2H, d,J=6.2 Hz), 7.22-7.48 (3H, m), 7.54-7.90 (3H, m)

ESI-MS (m/e, as (C₁₇H₂₂F₂N₂O₃+H)⁺): 341

EXAMPLE 82 3-((Iminomethyl)(methyl)amino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 3-(methylamino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.55-2.30 (8H, m), 2.95 (9/4H, s), 3.07 (3/4H, s),3.15-3.50 (3H, m), 4.10-4.34 (2H, m), 7.25-7.48 (3H, m), 7.56-7.80 (3H,m)

ESI-MS (m/e, as (C₁₈H₂₄F₂N₂O₃+H)⁺): 355

EXAMPLE 83 4-((Iminomethyl)amino)butyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using 4-aminobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 48. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.17-2.30 (10H, m), 3.14-3.40 (3H, m), 4.12-4.26(2H, m), 7.22-7.40 (3H, m), 7.55-7.66 (2H, m), 7.75-7.86 (1H, m)

ESI-MS (m/e, as (C₁₈H₂₄F₂N₂O₃+H)⁺): 355

EXAMPLE 84 (1-(Iminomethyl)piperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phehnylethanoatemonohydrochloride

Using piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylethanoate,the title compound was prepared through the treatments as in the methodof Example 48 The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.10-1.42 (3H, m), 1.68-1.92 (4H, m), 1.92-2.10(2H, m), 2.99-3.13 (2H, m), 3.22-3.48 (1H, m), 3.70-3.82 (1H, m),3.89-4.22 (4H, m), 7.25-7.41 (3H, m), 7.56-7.65 (2H, m), 7.75-7.91 (1H,m)

ESI-MS (m/e, as (C₂₀H₂₆F₂N₂O₄+H)⁺): 397

EXAMPLE 85 (1-Amidinopiperidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

To a solution of 14 mg of piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in0.020 ml of anhydrous dimethylformamide, 6.3 mg of1H-pyrazole-1-carboxamidine hydrochloride and 0.008 ml ofdiisopropylethylamine were added, followed by stirring at roomtemperature for 12 hours. The reaction liquid was condensed and dried tosolid. Thus obtained crude product was purified on silica gel columnchromatography (eluent: chloroform/methanol =10/1), to provide 11 mg ofthe title compound in the form of a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.08-2.22 (11H, m), 3.01 (2H, t, J=13.57 Hz), 3.24(1H, m), 3.82 (2H, m), 4.02 (1H, dd, J=6.12, 10.95 Hz), 4.10 (1H, dd,J=6.12, 10.95 Hz), 7.31 (3H, m), 7.60 (2H, d, J=7.10 Hz)

ESI-MS (m/e, as (C₂₀H₂₇F₂N₃O₃+H)⁺): 396

EXAMPLE 86 1-Amidinopiperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 85. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.61-1.82 (3H, m), 1.82-2.23 (7H, m), 3.22-3.52(6H, m), 5.08 (1H, m), 7.35 (3H, m), 7.63 (2H, dd, J=1.56, 7.05 Hz)

ESI-MS (m/e, as (C₁₉H₂₅F₂N₃O₃+H)⁺): 382

EXAMPLE 87 1,4,5,6-Tetrahydropyrimidin-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

To a solution of 18.6 mg of 2-thioxohexahydropyrimidin-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 1ml of ethanol, Raney-nickel was added, followed by 6 hours' stirring atambient temperature and pressure in hydrogen atmosphere. The reactionliquid was filtered with Celite. After adding 10% hydrochloricacid-methanol to the filtrate, the solvent was distilled off underreduced pressure to provide 15.4 mg of the title compound in the form ofa white solid.

¹H-NMR (CD₃OD, δppm): 1.55-2.20 (9H, m), 2.69 (1H, s), 3.20-3.40 (2H,m), 3.80 (1H, s), 4.23 (1H, dd, J=4.29, 11.8 Hz), 4.39 (1H, dd, J=4.29,11.8 Hz), 7.36 (3H, m), 7.59 (2H, d, J=7.10 Hz), 7.97 (1H, s)

ESI-MS (m/e, as (C₁₈H₂₂F₂N₂O₃+H)⁺): 353

EXAMPLE 88 (4S)-1,4,5,6-tetrahydropyrimidin-4-ylmetyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemonohydrochloride

Using ((4S)-2-thioxohexahydropyrimidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 87. The product was obtained as a colorless oily substance.

¹H-NMR (CD₃OD, δppm): 1.50-2.22 (9H, m), 3.20-3.40 (2H, m), 4.11-4.47(2H, m), 7.33 (3H, m), 7.61 (2H, d, J=7.1Hz), 7.98 (1H, s)

ESI-MS (m/e, as (C₁₈H₂₂F₂N₂O₃+H)⁺): 353

EXAMPLE 89 (4R)-1,4,5,6-tetrahydropyrimidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoatemono-hydrochloride

Using ((4R)-2-thioxohexahydropyrimidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared through the treatments as in the method ofExample 87. The product was obtained as a colorless solid.

¹H-NMR (CD₃OD, δppm): 1.54-2.26 (6H, m), 3.05-3.75 (5H, m), 5.39-5.48(1H, m), 7.20-7.47 (3H, m), 7.53-7.69 (2H, m), 7.93-8.18 (1H, m)

ESI-MS (m/e, as (C₁₇H₂₀F₂N₂O₃+H)⁺): 339

REFERENTIAL EXAMPLE 1(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid

(Step 1)

Synthesis of(2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-oneand(2R,5R)-2-(t-butyl)-5-((1S)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one

Following the method of D. Seebach, et al. [Tetrahedron, Vol. 40, pp.1313-1324 (1984)], (2R, 5R)-2-(t-butyl)-5-phenyl-1,3-dioxolan-4-one wassynthesized. To a liquid mixture of 20 ml of a tetrahydrofuran solutioncontaining 510 mg of the synthesized compound with 1 ml ofhexamethyl-phosphoric triamide, 1.7 ml of 1.5M hexane solution oflithium diisopropylamide was added dropwise at −78° C., stirred for 30minutes, then 1.5 ml of tetrahydrofuran solution containing 285 mg ofcyclopentenone was added, and the system was further stirred for 1.5hours. The reaction liquid was diluted with ethyl acetate, washedsuccessively with a saturated aqueous ammonium chloride solution, waterand saturated brine, and thereafter dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresultant residue was purified on medium pressure silica gel columnchromatography (eluent: hexane/ethyl acetate=15/1−10/1), to provide 150mg and 254 mg of the title compounds, respectively, as oily substances.Configuration of each of said compounds was determined from NOE of NMR.

(Step 2)

Synthesis of(2R,5R)-2-(t-butyl)-5-((1R)-3,3-difluoro-cyclopentyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 2.8 g of (2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in30 ml of chloroform, 4.89 ml of trifluorodiethylaminosulfuric acid wasadded under cooling with ice, followed by 20 hours' stirring at roomtemperature. The reaction liquid was diluted with chloroform, washedsuccessively with water and with saturated brine, and dried overanhydrous magnesium sulfate. Distilling the solvent off under reducedpressure, the resulting residue was purified on silica gel columnchromatography (eluent: hexane/ethyl acetate=20/1) to provide 2.4 g ofthe title compound.

(Step 3)

Synthesis of(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid

To a solution of 2.4 g of(2R,5R)-2-(t-butyl)-5-((1R)-3,3-difluorocyclopentyl)-5-phenyl-1,3-dioxolan-4-onein 30 ml of methanol, 10 ml of 1N aqueous sodium hydroxide solution wasadded, followed by 3 hours' stirring at room temperature. Distilling themethanol off under reduced pressure, the reaction liquid was dilutedwith water and washed with diethyl ether. The aqueous layer wasacidified with 1N hydrochloric acid and extracted from diethyl ether,and the organic layer was dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, 1.66 g of the titlecompound was obtained.

REFERENTIAL EXAMPLE 2(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid

(Step 1)

Synthesis of (2R, 5R)-2-(t-butyl)-5-(4-chlorophenyl)-1,3-dioxolan-4-one

To a solution of 16 g of (2R)-2-(4-chlorophenyl)-2-hydroxyacetic acid(cf. JP-Hei 6 (1994)-165695A) in 440 ml of hexane/toluene (10:1), 23 mlof pivalaldehyde and 326 mg of p-toluenesulfonic acid monohydrate wereadded by the order stated, followed by 12 hours' heating under refluxwhile removing the generated water with Dean-Stark trap. The reactionliquid was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, 14 g of the title compound was obtained.

(Step 2)

(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid

Using (2R,5R)-2-(t-butyl)-5-(4-chlorophenyl)-1,3-dioxolan-4-one, thetitle compound was prepared by a method similar to Referential Example1.

REFERENTIAL EXAMPLE 3(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)aceticacid

Using (2R)-2-(4-fluorophenyl)-2-hydroxyacetic acid (cf. JP-Hei6(1994)-165695A), the title compound was prepared by a method similar toReferential Example 2.

REFERENTIAL EXAMPLE 4(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid

Using (2R)-2-(bromophenyl)-2-hydroxyacetic acid (cf. JP-Hei 6-165695A),the title compound was prepared by a method similar to ReferentialExample 2.

REFERENTIAL EXAMPLE 5(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methoxyphenyl)aceticacid

(Step 1)

Synthesis of (2R)-2-methoxyphenyl-2-hydroxyacetic acid

To a solution of 19 g of methyl(2R)-2-(methoxyphenyl)-2-hydroxyethanoate (cf. Journal of ChemicalSociety, Parkintrans 1, 2253-2255 (1992)) in 50 ml of methanol, 50 ml of3N aqueous sodium hydroxide solution was added, followed by 12 hours'stirring at room temperature. Distilling the methanol off under reducedpressure, the reaction liquid was acidified with 1N hydrochloric acidand extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate and the solvent was distilled off under reducedpressure, to provide 11 g of the title compound.

(Step 2)

Synthesis of(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methoxyphenyl)aceticacid

Using (2R)-2-(methoxyphenyl)-2-hydroxyacetic acid, the title compoundwas prepared by a method similar to Referential Example 2.

REFERENTIAL EXAMPLE 6(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)aceticacid

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)aceticacid (cf. JP-Hei 6-165695A), the title compound was prepared by a methodsimilar to Referential Example 2.

REFERENTIAL EXAMPLE 7(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hvdroxy-2-(2,4-difluorophenyl)aceticacid

(Step 1)

Synthesis of methyl (2R)-2-(2,4-difluorophenyl)-2-hydroxyethanoate

T. Miyazawa, et al. 's method [Journal of Chemical Society, Parkin trans1, 2253-2255 (1992)] was used. To a solution of 3.9 g of2-(2,4-difluorophenyl)-2-hydroxyacetec acid in 20 ml of diisopropylether, 20 ml of vinyl acetate and 2 g of Lipase AK were added, followedby 13 days' stirring at room temperature. The precipitate was removed byfiltration with Celite, and the solvent was distilled off from thefiltrate under reduced pressure. The residue was purified on silica gelcolumn chromatography (eluent: hexane-hexane/ethyl acetate=2/1) toprovide 2.4 g of the title compound.

(Step 2)

Synthesis of(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)aceticacid

Using (2R)-2-(2,4-difluorophenyl)-2-hydroxyacetic acid, the titlecompound was prepared by a method similar to Referential Example 5.

REFERENTIAL EXAMPLE 8(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl)aceticacid

Using (2R)-2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (cf. JP-Hei6-165695A), the title compound was prepared by a method similar toReferential Example 2.

REFERENTIAL EXAMPLE 9(2R)-2-((1R)-3-fluorocyclopentyl)-2-hydroxy-2-phenylacetic acid

(Step 1)

Synthesis of (2R,5R)-2-(t-butyl)-5-((1R)-3-hydroxy-cyclopentyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 169 mg of the(2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one,as obtained in Step 1 of Referential Example 1, in 2 ml of methanol, 71mg of sodium borohydride was added under cooling with ice, followed by30 minutes' stirring at the same temperature. The reaction liquid wasdiluted with diethyl ether, washed with water and with saturated brine,and dried over anhydrous magnesium sulfate. Distilling the solvent offunder reduced pressure, 157 mg of the title compound was obtained as acolorless oily substance.

(Step 2)

Synthesis of (2R)-2-((1R)-3-fluorocyclopentyl)-2-hydroxy-2-phenylaceticacid

Using(2R,5R)-2-(t-butyl)-5-((1R)-3-hydroxycyclopentyl)-5-phenyl-1,3-dioxolan-4-one,the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 1.

REFERENTIAL EXAMPLE 10(2R)-2-((1S)-3-fluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)-aceticacid

Using the (2R,5R)-2-(t-butyl)-5-((1S)-3-oxocyclopentyl)-5-(4-chlorophenyl)-1,3-dioxolan-4-oneas obtained in Referential Example 2, the title compound was prepared bya method similar to Referential Example 9.

REFERENTIAL EXAMPLE 11(2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylaceticacid

(Step 1)

Synthesis of(4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-1-cyclopentenylacetate and(3R)-3-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-1-cyclopentenylacetate

To a solution of 185 mg of(2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-onein 1 ml of vinyl acetate, 10 mg of p-toluenesulfonic acid monohydratewas added, followed by 12 hours' heating under reflux. Distilling thesolvent off under reduced pressure, the residue obtained was purified onsilica gel column chromatography (eluent: hexane−hexane/ethylacetate=15/1) to provide 184 mg of the title compounds as a mixture ofthe two compounds.

(Step 2)

Synthesis of(2R,5R)-2-(t-butyl)-5-((1R,3R)-3-hydroxy-4-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one

To a solution of 169 mg of(4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-1-cyclopentenylacetate in 7.5 ml of acetonitrile and water (2:1), 80 mg of N-methylmorpholine-oxide and 0.2 ml of 2% aqueous osmium tetraoxide solutionwere successively added at 0° C. by the order stated, followed by 3hours' stirring at the same temperature. Sodium sulfite was added to thereaction liquid and stirred for further 30 minutes. The reaction liquidwas then diluted with ethyl acetate, washed successively with water andsaturated brine, and dried over anhydrous sodium sulfate. Distilling thesolvent off under reduced pressure, the residue obtained was purified onsilica gel column chromatography (eluent: hexane−hexane/ethylacetate=2/1) to provide 32 mg of the title compound as a colorlesssolid.

(Step 3)

Synthesis of(1R,4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-2-oxocyclopentylacetate

To a solution of 32 mg of(2R,5R)-2-(t-butyl)-5-((1R,3R)-3-hydroxy-4-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-onein 1 ml of pyridine, 0.5 ml of acetic anhydride was added, followed by 1hour's stirring at room temperature. The reaction liquid was dilutedwith ethyl acetate, washed successively with water, 1N hydrochloric acidand saturated brine, and dried over anhydrous sodium sulfate. Distillingthe solvent off under reduced pressure, the residue obtained waspurified on preparative thin layer chromatography (Kieselgel™ 60F₂₅₄,Art 5744 (Merck), chloroform/acetone=20/1) to provide 27 mg of the titlecompound as a colorless oily substance.

(Step 4)

Synthesis of(2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclo-pentyl)-2-hydroxy-2-phenylaceticacid

Using the(1R,4R)-4-((2R,4R)-2-(t-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl)-2-oxocyclopentylacetate as obtained in Step 3, the title compound was prepared bytreating it by a method similar to Steps 2 and 3 of Example 1.

REFERENTIAL EXAMPLE 12 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of 4-hydroxy-1-t-butoxycarbonylpiperidine

To a solution of 10 g of 4-hydroxypiperidine in 300 ml of chloroform, 20g of di-t-butylcarbonate was added under cooling with ice, followed by 2hours' stirring at room temperature. The reaction liquid was dilutedwith ethyl acetate, washed successively with water and saturated brine,and dried over anhydrous sodium sulfate. Distilling the solvent offunder reduced pressure, 18 g of the title compound was obtained.

(Step 2)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyloxy)tetrahydropyridine-1(2H)-carboxylate

To a solution of 128 mg of(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylacetic acid in3 ml of dimethylformamide, 81 mg of carbonyldiimidazole was added andstirred for 30 minutes. Then 121 mg of4-hydroxy-1-t-butoxycarbonylpiperidine and 10 mg of sodium hydride wereadded successively, followed by another 30 minutes' stirring. Thereaction liquid was diluted with ethyl acetate, washed successively withwater and saturated brine, and dried over anhydrous sodium sulfate.Distilling the solvent off under reduced pressure, the residue obtainedwas purified on silica gel column chromatography (eluent: hexane/ethylacetate=3/1) to provide 121 mg of the title compound.

(Step 3)

Synthesis of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

162 Milligrams of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoyloxy)tetrahydropyridine-1(2H)-carboxylatewas dissolved in 5 ml of 10% hydrochloric acid-methanol, stirred for 12hours, and the solvent was distilled off under reduced pressure. Theresidue was diluted with water, washed with diethyl ether and asaturated aqueous sodium hydrogencarbonate solution was added to theaqueous layer to render it alkaline. Following an extraction with ethylacetate, the organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. Distilling the solvent off under reducedpressure, 104 mg of the title compound was obtained as a colorless,foamy substance.

REFERENTIAL EXAMPLE 13 Pyperidin-4-ylmethyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of ethyl N-t-butoxycarbonyl-isonipecotate

Using ethyl isonipecotate, the title compound was prepared by a methodsimilar to Step 1 of Referential Example 12.

(Step 2)

Synthesis of N-t-butoxycarbonyl-4-piperidinemethanol

To a solution of 516 mg of ethyl N-t-butoxycarbonyl-isonipecotate in 30ml of tetrahydrofuran, 200 mg of lithium-aluminum hydride was addedunder cooling with ice, followed by 20 minutes' stirring at the sametemperature. Sodium sulfate decahydrate was added to the reactionliquid, stirred for 30 minutes and filtered with Celite. Distilling thesolvent off under reduced pressure, 414 mg of the title compound wasobtained.

(Step 3)

Synthesis of pyperidin-4-ylmethyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using N-t-butoxycarbonyl-4-piperidinemethanol, the title compound wasprepared by a method similar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 14 2-(Piperidin-4-yl)ethyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl4-(2-ethoxy-2-oxoethylidene)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 9.1 g of 60% oily sodium hydride in 200 ml oftetrahydrofuran, 38.0 ml of ethyl diethylphosphonoacetate was addeddropwise under cooling with ice, stirred for 20 minutes, and thereaftera solution of 31.4 g of 1-t-butoxycarbonyl-4-piperidone in 500 ml oftetrahydrofuran was added dropwise, followed by 40 minutes' stirring atthe same temperature. The reaction liquid was diluted with ethylacetate, washed successively with aqueous ammonium chloride solution,water and saturated brine, and dried over anhydrous sodium sulfate.Distilling the solvent off under reduced pressure, the residue wasrecrystallized from methanol to provide 33.5 g of the title compound.

(Step 2)

Synthesis of t-butyl4-(2-ethoxy-2-oxoethyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 355 mg of t-butyl4-(2-ethoxy-2-oxoethylidene)tetrahydropyridine-1(2H)-carboxylate in 10ml of methanol, 50 mg of 10% palladium-on-carbon catalyst was added andstirred for 13 hours in 3 atmospheres' hydrogen pressure. Filtering thecatalyst off, the solvent was distilled off under reduced pressure toprovide 334 mg of the title compound.

(Step 3)

Synthesis of t-butyl4-(2-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate

To a solution of 2'mg of t-butyl4-(2-ethoxy-2-oxoethyl)-tetrahydropyridine-1(2H)-carboxylate in 15 ml oftetrahydrofuran, 100 mg of lithiumaluminum hydride was added undercooling with ice, followed by 20 minutes' stirring at the sametemperature. To the reaction liquid sodium sulfate decahydrate wasadded, stirred for 30 minutes and filtered with Celite. Distilling thesolvent off under reduced pressure, 207 mg of the title compound wasobtained.

(Step 4)

Synthesis of 2-(piperidin-4-yl)ethyl(2R)-((1R)-3,3-difluoro-cyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 4-(2-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate,the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 15 3-(Piperidin-4-yl)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl4-(3-ethoxy-3-oxopropyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 1.0 g of t-butyl4-(3-ethoxy-3-oxoprop-1-enyl)-tetrahydropyridine-1(2H)-carboxylate (cf.WO9501336) in 20 ml of ethanol, 300 mg of 10% palladium-on-carboncatalyst, and stirred for 3 hours in a hydrogen atmosphere, at ambienttemperature and pressure. After filtering the catalyst off, the solventwas distilled off under reduced pressure to provide 700 mg of the titlecompound.

(Step 2)

Synthesis of t-butyl4-(3-hydroxypropyl)tetrahydropyridine-1(2H)-carboxylate

Using t-butyl4-(3-ethoxy-3-oxopropyl)tetrahydro-pyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to Step 3 of ReferentialExample 14.

(Step 3)

Using t-butyl 4-(3-hydroxypropyl)tetrahydropyridine-1(2H)-carboxylate,the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12. REFERENTIAL EXAMPLE 161,2,3,6-Tetrahydropyridin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate(cf. WO9806720), the title compound was prepared by a method similar toSteps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 17 2-(4-Piperidinylidene)ethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl4-(2-hydroxyethylidene)tetrahydropyridine-1(2H)-carboxylate (cf.WO9940070), the title compound was prepared by a method similar to Steps2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 18 2-(1,2,3,6-Tetrahydropyridin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 4-(2-hydroxyethyl)-3,6-dihydropyridine-1(2H)-carboxylate(cf. WO9806720), the title compound was prepared by a method similar toSteps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 19 (3R)-piperidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (3R)-3-(hydroxymethyl)tetrahydropyridine-1(2H)-carboxylate(cf Tetrahedron Asymmetry, Vol. 3, p. 1049 (1992)), the title compoundwas prepared by a method similar to Steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 20 2-((3R)-piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl(3R)-3-(2-ethoxy-2-oxoethyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 1.15 g of ethyl 2-((3R)-piperidin-3-yl)acetateL-(+)-mandelate (cf. JP-Hei 10 (1998)-508321A) in 20 ml of dioxane, 780mg of di-t-butyl-dicarbonate and 10 ml of 10% aqueous potassiumcarbonate solution were added, followed by 30 minutes' stirring at roomtemperature. The reaction liquid was diluted with diethyl ether, washedwith saturated brine and dried over anhydrous magnesium sulfate.Distilling the solvent off under reduced pressure, 985 mg of the titlecompound was obtained.

(Step 2)

Synthesis of t-butyl(3R)-3-(2-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 143 mg of t-butyl (3R)-3-(2-ethoxy-2-oxoethyl)tetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran, 30 mgof litiumaluminum hydride was added under cooling with ice, followed by20 minutes' stirring at the same temperature. To the reaction liquidsodium sulfate decahydrate was added, stirred for 12 hours and filteredwith Celite. Distilling the solvent off under reduced pressure, 118 mgof the title compound was obtained.

(Step 3)

Synthesis of 2-((3R)-piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl(3R)-3-(2-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 21 2-((3S)-piperidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using ethyl 2-((3S)-piperidin-3-yl)acetate D-(−)-mandelate (cf. JP-Hei10 (1998)-508321A), the title compound was prepared by a method similarto Referential Example 20.

REFERENTIAL EXAMPLE 22 (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (cf. Syn. Commun.,Vol. 15, p. 587 (1985)), the title compound was prepared by a methodsimilar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 23 (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-2-phenylethanoate

Using t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (cf. Syn. Commun.,Vol. 15, p. 587 (1985)), the title compound was prepared by a methodsimilar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 24 (3R)-pyrrolidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (cf.JP96-107364), the title compound was prepared by a method similar toSteps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 25 (3S)-pyrrolidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (cf.JP96-107364), the title compound was prepared by a method similar toSteps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 26 2-((3S)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of methyl 2-(3S)-5-oxo-1-((1R)-1-phenylethyl)-pyrrolidin-3-ylacetate

To a solution of 100 mg of(4R)-4-(hydroxymethyl)-1-((1R)-1-phenylethyl)pyrrolidin-2-one (cf.Heterocycles, Vol. 51, 2463-2470 (1999)) in 2 ml of chloroform, 0.075 mlof triethylamine and 0.041 ml of methanesulfonyl chloride were added,followed by 2 hours' stirring at room temperature. The reaction liquidwas diluted with chloroform, washed successively with saturated aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, 49 mg of sodium cyanide was added to the residue as dissolvedin 2 ml of dimethyl sulfoxide, and stirred for 3 hours at 80° C. Thereaction liquid was diluted with chloroform, washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was dissolved in 2ml of conc. hydrochloric acid, heated under reflux for 20 hours, andwater was removed under reduced pressure. Adding 5 ml of 10%hydrochloric acid-methanol to the residue, heating under reflux wascontinued for further 12 hours, and the solvent was distilled off underreduced pressure. The residue was rendered alkaline by addition ofaqueous sodium hydrogencarbonate solution, and then extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate.Distilling the solvent off under reduced pressure, 90 mg of the titlecompound was obtained.

(Step 2)

Synthesis of 2-((3S)-1-((1R)-1-phenylethyl)pyrrolidin-3-yl)-ethylacetate

To a solution of 90 mg of methyl 2-(3S)-5-oxo-1-((1R)-1-phenylethyl)pyrrolidin-3-ylacetate in 2 ml of tetrahydrofuran, 25 mg oflithiumaluminum hydride was added under cooling with ice, followed by 2hours' heating under reflux. To the reaction liquid sodium sulfatedecahydrate was added, stirred for 45 minutes, filtered with Celite andthe solvent was distilled off under reduced pressure. To 1 ml ofchloroform solution of the resulting residue, 0.060 ml of triethylamineand 0.040 ml of acetic anhydride were added, followed by 5 hours'standing at room temperature. The reaction liquid was diluted with ethylacetate, washed successively with saturated aqueous sodiumhydrogencarbonate solution and saturated brine, and dried over anhydroussodium sulfate. Distilling the solvent off under reduced pressure, theresidue was purified on silica gel column chromatography (eluent:chloroform/methanol=10/1) to provide 64 mg of the title compound.

(Step 3)

Synthesis of t-butyl(3S)-3-(2-(acetyloxy)ethyl)pyrrolidine-1-carboxylate

To a solution of 64 mg of2-((3S)-1-((1R)-1-phenylethyl)-pyrrolidin-3-yl) ethyl acetate in 5 ml ofmethanol, 64 mg of palladium hydroxide-carbon was added, and stirred for21 hours at ambient temperature under 3 atmospheres of hydrogenpressure. The reaction liquid was filtered with Celite, the solvent wasdistilled off under reduced pressure, and the residue was dissolved in 1ml of chloroform. To the solution 78 mg of di-t-butyl-dicarbonate and0.035 ml of triethylamine were added and stirred for 3 hours at roomtemperature. The reaction liquid was diluted with chloroform, washedsuccessively with water and saturated brine, and dried over anhydroussodium sulfate. Distilling the solvent off under reduced pressure, theresulting residue was purified on silica gel column chromatography(eluent: ethyl acetate/hexane=2/1) to provide 34 mg of the titlecompound.

(Step 4)

Synthesis of t-butyl (3S)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate

To a solution of 34 mg of t-butyl(3S)-3-(2-acetyloxyethyl)-pyrrolidine-1-carboxylate in 1 ml of methanol,54 mg of potassium carbonate was added, and stirred for 2.5 hours atroom temperature. The reaction liquid was diluted with chloroform,washed successively with water and saturated brine and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, 29 mg of the title compound was obtained.

(Step 5)

Synthesis of 2-((3S)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (3S)-3-(2-hydroxyethyl) pyrrolidine-1-carboxylate, thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 27 2-((3R)-pyrrolidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using (4S)-4-(hydroxymethyl)-1-((1R)-1-phenylethyl)-pyrrolidin-2-one,the title compound was prepared by a method similar to ReferentialExample 26.

REFERENTIAL EXAMPLE 28 (2R)-pyrrolidin-2-ylmethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 29 Azetidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 3-hydroxyazetidine-1-carboxylate (cf. WO9742189), thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 30 Azetidin-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 3-(hydroxymethy1)azetidine-1-carboxylate (Eur. J. Med.Chem., Vol. 34, 363-380 (1999)), the title compound was prepared by amethod similar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 31 2-(Azetidin-3-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (cf. WO9412181),the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 32 3-Endo-8-azabicyclo[3.2.]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 3-endo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate(cf. Drug Metab. Dispos., Vol. 20, 596-602 (1992)), the title compoundwas prepared by a method similar to Steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 33 3-Azabicyclo[3.3.1]non-9-yl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 9-hydroxy-3-azabicyclo[3.3.1]nonane-3-carboxylate, thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 34 3-Exo-8-azabicyclo[3.2.1]oct-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of 3-exo-8-benzyl-8-azabicyclo[3.2.1]octane-3-carbonitrile

To a solution of 332 mg of 8-benzyl-8-azabicyclo[3.2.1]oct-3-one in 9 mlof dimethoxyethane, 550 mg of tosylmethyl isocyanate, 0.25 ml of ethanoland potassium t-butoxide were successively added at 0° C., followed by 5hours' stirring at 50° C. The reaction liquid was diluted with ethylacetate, washed with saturated brine and dried over anhydrous sodiumsulfate. Distilling the solvent off under reduced pressure, theresulting residue was purified on silica gel column chromatography(eluent: hexane/ethyl acetate=1/1, to provide 236 mg of the titlecompound

(Step 2)

Synthesis of methyl3-exo-8-benzyl-8-azabicyclo[3.2.1]octane-3-carboxylate

236 Milligrams of 8-benzyl-8-azabicyclo[3.2.1]octane-3-carbonitrile wasdissolved in 3 ml of conc. hydrochloric acid, and after 12 hours'heating under reflux, water was distilled off under reduced pressure.The resulting residue was dissolved in 10% hydrochloric acid-methanol,and heated under reflux for 2 hours. Distilling the solvent off underreduced pressure, the residue was diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium hydrogencarbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Distillingthe solvent off under reduced pressure, the resulting residue waspurified on silica gel column chromatography (eluent: hexane/ethylacetate=1/1) to provide 225 mg of the title compound.

(Step 3)

Synthesis of (3-exo-8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using methyl 3-exo-8-benzyl-8-azabicyclo[3.2.1]octane-3-carboxylate, thetitle compound was prepared by a method similar to Step 2 of ReferentialExample 13 and Step 2 of Referential Example 12.

(Step 4)

Synthesis of 3-exo-8-azabicyclo[3.2.1]oct-3-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a solution of 82 mg of(3-exo-8-benzyl-8-azabicyclo-[3.2.1]oct-3-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 5ml of methanol, 15 mg of palladium hydroxide-carbon catalyst was added,and stirred for 2 hours at ambient temperature and pressure in hydrogenatmosphere. The reaction liquid was filtered with Celite, and thesolvent was distilled off under reduced pressure to provide 55 mg of thetitle compound.

REFERENTIAL EXAMPLE 35 (3aR,6aS)-octahydrocyclopenta(c)pyrrol-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl(3aR,6aS)-5-hydroxyhexahydrocyclopenta[c]-pyrrole-2(1H)-carboxylate (cf.WO9806720), the title compound was prepared by a method similar to Steps2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 36 2,4-Cis-2-vinylpiperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl2,4-cis-4-hydroxy-2-vinyltetrahydropyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 37 (4-Hydroxypiperidin-4-yl)methyl(2R)-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl 4-methylenetetrahydropyridine-1(2H)-carboxylate

To a solution of 986 mg of methyltriphenylphosphonium bromide in 20 mlof tetrahydrofuran, 1.87 ml of 1.63 M n-butyl lithium/hexane solutionwas added dropwise at 0° C., under cooling with ice. The temperaturethen was immediately raised to room temperature, and the system wasstirred for 50 minutes. The reaction liquid was again cooled to 0° C.,to which a solution of 500 mg of t-butyl4-oxotetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran wasadded dropwise, followed by an hour's stirring at the same temperature.The reaction liquid was diluted with ethyl acetate, washed successivelywith saturated aqueous ammonium chloride solution and saturated brine,and dried over anhydrous sodium sulfate. Distilling the solvent offunder reduced pressure, the resulting residue was purified on silica gelcolumn chromatography (eluent: hexane/ethyl acetate=5/1) to provide 192mg of the title compound.

(Step 2)

Synthesis of t-butyl4-hydroxy-4-(hydroxymethyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 98 mg of t-butyl4-methylenetetrahydro-pyridine-1(2H)-carboxylate in 2 ml oftetrahydrofuran-water (1:1), 88 mg of N-methyl morpholine-oxide and 0.1ml of 2% osmium tetraoxide were added at 0° C., followed by 2 hours'stirring at the same temperature. Adding sodium sulfite to the reactionliquid, the reaction liquid was further stirred for 30 minutes, dilutedwith ethyl acetate, washed successively with water and saturated brine,and dried over anhydrous sodium sulfate. Distilling the solvent offunder reduced pressure, 115 mg of the title compound was obtained.

(Step 3)

Synthesis of (4-hydroxypiperidin-4-yl)methyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl4-hydroxy-4-(hydroxymethyl)tetrahydro-pyridine-1(2H)-carboxylate, thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 38 (1R)-1-Piperidin-4-ylethyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl4-((1S)-1-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 103 mg of (R)-(+)-α-methyl-4-pyridine-methanol in 6 mlof 2% hydrochloric acid-methanol, 10 mg of platinum oxide was added,followed by 1.5 hours' stirring at room temperature in hydrogenatmosphere of 4 atmospheric pressure. The reaction liquid was filteredwith Celite, the solvent was distilled off under reduced pressure, andthe resulting residue was dissolved in 6 ml of dioxane. To the solution78 mg of di-t-butyl-dicarbonate and 4 ml of 1N sodium hydroxide wereadded, followed by 1 hour's stirring at room temperature. The reactionliquid was diluted with chloroform, washed successively with water andsaturated brine, and dried over anhydrous sodium sulfate. Distilling thesolvent off under reduced pressure, the resulting residue was purifiedon silica gel column chromatography (eluent: ethyl acetate/hexane=2/1)to provide 46 mg of the title compound.

(Step 2)

Using t-butyl4-((1S)-1-hydroxyethyl)tetrahydropyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12. REFERENTIAL EXAMPLE 39 2-Piperadinoethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenlethanoate

Using t-butyl 4-(2-hydroxyethyl)tetrahydropyrazine-1(2H)-carboxylate,the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 40 2-Aminoethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 2-hydroxyethylcarbamate, the title compound was preparedby a method similar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 41 3-Aminopropyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 3-hydroxypropylcarbamate, the title compound was preparedby a method similar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 42 3-(Methylamino)propyl(2R)-2-((1R)-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of 3-(benzylamino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a methanol solution of 87 mg of 3-aminopropyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 35 mgof benzaldehyde was added at room temperature, stirred for 30 minutes atthe same temperature, sodium borohydride was added, and further stirredfor 30 minutes. The reaction liquid was diluted with ethyl acetate,washed successively with saturated aqueous sodium hydrogencarbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.Distilling the solvent off under reduced pressure, the resulting residuewas purified on silica gel column chromatography (eluent:chloroform/methanol=50/1), to provide the title compound.

(Step 2)

Synthesis of 3-(benzyl(methyl)amino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using 3-(benzylamino)propyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate, thetitle compound was prepared by a method similar to Step 1 of Example 1.

(Step 3)

Synthesis of 3-(methylamino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

To a solution of 41 mg of 3-(benzyl(methyl)amino)propyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 2ml of methanol, 10 mg of palladium hydroxide-carbon catalyst was added,followed by 2 hours' stirring at ambient temperature and pressure inhydrogen atmosphere. The reaction liquid was filtered with Celite.Distilling the solvent off from the filtrate under reduced pressure, 32mg of the title compound was obtained.

REFERENTIAL EXAMPLE 434-Aminobutyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl 4-hydroxybutylcarbamate, the title compound was preparedby a method similar to Steps 2 and 3 of Referential Example 12.

REFERENTIAL EXAMPLE 44 1,4-Trans-4-aminocyclohexyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl N-(trans-4-hydroxycyclohexyl)carbamate (cf. WO9424093),the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 45 1,4-Cis-4-aminocyclohexyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl N-(cis-4-hydroxycyclohexyl)carbamate (cf. WO9424093), thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 46 1,3-Ttrans-3-aminocyclobutyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl N-(trans-3-hydroxycyclobutyl)carbamate (cf. WO9424093),the title compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 47 1,3-Cis-3-aminocyclobutyl(2R)-2-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl N-(cis-3-hydroxycyclobutyl)carbamate (cf. WO9424093), thetitle compound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 48 (1S,4S)-4-amino-2-cyclopentenyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl N-((1S,4S)-4-hydroxy-2-cyclopentenyl)-carbamate (cf.Journal of Medicinal Chemistry, Vol. 35, 3196 (1992), the title compoundwas prepared by a method similar to Steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 49 (1R,3R)-3-aminocyclopentyl(2R)-2-((1R)-3.3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of t-butyl(1R,3R)-3-((2R)-2-((1R)-3,3-difluorocyclopentane)-2-hydroxy-2-phenylethanoyloxy)cyclopentyl-1-carboxylate

To a solution of 66 mg of the t-butyl(1R,3R)-3-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyloxy)-2-cyclopentenyl-1-carboxylateas obtained in Referential Example 48 in 2 ml of methanol, 10 mg ofpalladium-on-carbon catalyst was added, followed by an hour's stirringat ambient temperature and pressure in hydrogen atmosphere. The reactionliquid was filtered with Celite. Distilling the solvent off underreduced pressure, 28 mg of the title compound was obtained.

(Step 2)

Synthesis of (1R,3R)-3-aminocyclopentyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using t-butyl(1R,3R)-3-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoyloxy)cyclopentane-1-carboxylate,the title compound was prepared by a method similar to Step 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 50 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 51 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 52 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 53 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 54 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2-chlorophenyl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 55 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(1,3-benzodioxol-5-yl)aceticacid, the title compound was prepared by a method similar to Steps 2 and3 of Referential Example 12.

REFERENTIAL EXAMPLE 56 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoate

(Step 1)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate

To a solution of 125 mg of the t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylateas obtained in Referential Example 52 in 4 ml of dioxane, 0.10 ml ofvinyl tri-n-butyltin and 20 mg of tetrakistriphenylpalladium were addedat room temperature, followed by 24 hours' heating under reflux at 110°C. in nitrogen atmosphere. Distilling the solvent off under reducedpressure, the resulting residue was diluted with ethyl acetate, washedsuccessively with water and saturated brine, and dried over anhydroussodium sulfate. Distilling the solvent off under reduced pressure, theresidue was purified on silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to provide 90 mg of the title compound.

(Step 2)

Using t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate,the title compound was prepared by a method similar to Step 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 57 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoate

(Step 1)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate

To a solution of 50 mg of the t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylateas obtained in Referential Example 56 in 3 ml of methanol, 10 mg ofpalladium-on-carbon catalyst was added, followed by 6 hours' stirring atambient temperature and pressure in hydrogen atmosphere. The reactionliquid was filtered with Celite, and the solvent was distilled off underreduced pressure to provide the title compound.

(Step 2)

Using t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate,the title compound was obtained by a method similar to Step 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 58 Piperidin-4-yl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoate

(Step 1)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-(hydroxymethyl)phenyl)ethanoyloxy)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 69 mg of the t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylateas obtained in Referential Example 56 in 2 ml of tetrahydrofuran-water(1:1), 85 mg of sodium periodide and 0.1 ml of 2% osmium tetraoxide wereadded at 0° C., followed by an hour's stirring at the same temperature.Adding sodium sulfite to the reaction liquid, stirring was continued forfurther 30 minutes. The reaction liquid was diluted with ethyl acetate,washed successively with water and saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, the residue was dissolved in 1 ml of methanol. To the solution10 mg of sodium borohydride was added, stirred for 10 minutes andacetone was added. The reaction liquid was diluted with ethyl acetate,washed successively with water and saturated brine, and dried overanhydrous sodium sulfate. Distilling the solvent off under reducedpressure, the resulting residue was purified on preparative thin layerchromatography (Kieselgel™ 60F₂₅₄, Art 5744 (Merck), hexane/ethylacetate=1/1) to provide 42 mg of the title compound as a colorless oilysubstance.

(Step 2)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-((acetyloxy)methyl)phenyl)ethanoyloxy)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 42 mg of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-(hydroxymethyl)phenyl)-ethanoyloxy)tetrahydropyridine-1(2H)-carboxylatein 2 ml of chloroform, 0.015 ml of triethylamine, 0.01 ml of aceticanhydride and 2 mg of dimethylaminopyridine were added successively,followed by an hour's stirring at room temperature. The reaction liquidwas diluted with ethyl acetate, washed successively with water andsaturated brine, and dried over anhydrous sodium sulfate. Distilling thesolvent off under reduced pressure, the resulting residue was purifiedon preparative thin layer chromatography (Kieselgel™ 60F₂₅₄, Art 5744(Merck), hexane/ethyl acetate=2/1) to provide 42 mg of the titlecompound as a colorless oily substance.

(Step 3)

Synthesis of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoyloxy)tetrahydro-pyridine-1(2H)-carboxylate

To a solution of 42 mg of t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-((acetyloxy)methyl)phenyl)-ethanoyloxy)tetrahydropyridine-1(2H)-carboxylatein 1 ml of methanol, 20 mg of palladium hydroxide-carbon catalyst wasadded, followed by 16 hours' stirring at ambient temperature andpressure in hydrogen atmosphere. The reaction liquid was filtered withCelite and the solvent was distilled off under reduced pressure toprovide 37 mg of the title compound.

(Step 4)

Synthesis of piperidin-4-yl(2R)-((1R)-3,3-difluorocyclo-pentyl)-2-hydroxy-2-(4-methylphenyl)ethanoate

Using t-butyl4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoyloxy)tetrahydropyridine-1(2H)-carboxylate,the title compound was obtained by a method similar to Step 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 59 Piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compoundwas prepared by a method similar to Steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 60 Piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compoundwas prepared by a method similar to Steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 61 Piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoate

Using the t-butyl4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyloxy)methyl)tetrahydropyridine-1-(2H)-carboxylateas obtained in Referential Example 60, the title compound was preparedby a method similar to Referential Example 56.

REFERENTIAL EXAMPLE 62 Piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoate

Using the t-butyl4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)methyl)tetrahydropyridine-1-(2H)-carboxylateas obtained in Referential Example 61, the title compound was preparedby a method similar to Referential Example 58.

REFERENTIAL EXAMPLE 63 Piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-ethylphenyl)ethanoate

Using the t-butyl4-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-vinylphenyl)ethanoyloxy)methyl)tetrahydropyridine-1-(2H)-carboxylateas obtained in Referential Example 61, the title compound was preparedby a method similar to Referential Example 57.

REFERENTIAL EXAMPLE 64 Piperidin-4-ylmethyl(2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylethanoate

Using(2R)-2-((1R,4R)-3,3-difluoro-4-hydroxycyclopentyl)-2-hydroxy-2-phenylaceticacid and N-t-butoxycarbonyl-4-piperidine-methanol, the title compoundwas prepared by a method similar to steps 2 and 3 of Referential Example12.

REFERENTIAL EXAMPLE 65 2-(Piperidin-4-yl)ethyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid and t-butyl4-(2-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 66 2-(Piperidin-4-yl)ethyl(2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid and t-butyl4-(2-hydroxyethyl)tetrahydro-pyridine-1(2H)-carboxylate, the titlecompound was prepared by a method similar to steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 67 3-Endo-8-azabicyclo[3.2.]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid and t-butyl3-endo-3-hydroxy-8-azabicyclo-[3.2.1]octane-8-carboxylate, the titlecompound was prepared by a method similar to steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 68 3-Endo-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3.3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid and t-butyl3-endo-3-hydroxy-8-azabicyclo-[3.2.1]octane-8-carboxylate, the titlecompound was prepared by a method similar to steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 69 3-Endo-8-azabicyclo[3.2.1]oct-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(2,4-difluorophenyl)aceticacid and t-butyl3-endo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, the titlecompound was prepared by a method similar to steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 70 (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)aceticacid and t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 71 (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorohenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid and t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 72 (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid and t-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 73 (3R)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-methylphenyl)ethanoate

Using the t-butyl(3R)-3-(((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyl)oxy)-pyrrolidine-1-carboxylateas obtained in Referential Example 72, the title compound wassynthesized by a method similar to Step 1 of Referential Example 56 andReferential Example 57.

REFERENTIAL EXAMPLE 74 (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)aceticacid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 75 (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)aceticacid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 76 (3S)-pyrrolidin-3-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate

Using(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)aceticacid and t-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate, the titlecompound was prepared by a method similar to Steps 2 and 3 ofReferential Example 12.

REFERENTIAL EXAMPLE 77 ((4S)-2-thioxohexahydropyrimidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

(Step 1)

Synthesis of 2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol

To a solution of 1.0 g of methyl2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate in 29 ml of diethylether, 110 mg of lithium aluminum hydride was added under cooling withice, followed by 12 hours' stirring at the same temperature. Sodiumsulfate decahydrate was added to the reaction liquid which was thenstirred for 30 minutes and filtered with Celite. Distilling the solventoff under reduced pressure, 782 mg of the title compound was obtained.

(Step 2)

Synthesis of 1,2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-ethylazide

To a solution of 782 mg of2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol in 21 ml of ethylacetate, 1.5 ml of triethylamine and 643 mg of methanesulfonyl chloridewere added, followed by 30 minutes' stirring at room temperature. Thereaction liquid was diluted with ethyl acetate, washed successively withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,and dried over anhydrous sodium sulfate. Distilling the solvent offunder reduced pressure, the residue was dissolved in 25 ml ofdimethylformamide. To the solution 670 mg of sodium azide was added,followed by 12 hours' stirring at 90° C. The reaction liquid was dilutedwith ethyl acetate, washed successively with saturated aqueous ammoniumchloride solution and saturated brine, and dried over anhydrousmagnesium sulfate. Distilling the solvent off under reduced pressure,the resulting residue was purified on silica gel column chromatography(eluent: hexane/ethyl acetate=5/1) to provide 702 mg of the titlecompound.

(Step 3)

Synthesis of 1-((3R)-4-t-butyl(dimethyl)silyl)oxy-3-hydroxybutyl)azide

To a solution of 2.2 g of1,2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-ethylazide in 15 ml oftetrahydrofuran, 6 ml of 2N hydrochloric acid was added, followed by 2hours' stirring at room temperature. Distilling the solvent off underreduced pressure, the resulting residue was dissolved in 25 ml ofdimethylformamide. To the solution 2.0 g oft-butyl-dimethylsilylchloride and 1.8 g of imidazole were added,followed by 19 hours' stirring at room temperature. The reaction liquidwas diluted with ethyl acetate, washed successively with water andsaturated brine, and dried over anhydrous sodium sulfate. Distilling thesolvent off under reduced pressure, the resulting residue was purifiedon silica gel column chromatography (eluent: hexane/ethyl acetate=30/1)to provide 1.6 g of the title compound.

(Step 4)

Synthesis of1-((1S)-1-((t-butyl(dimethyl)silyl)oxymethyl)-3-triaza-1,2-dien-2-iumylpropyl)azide

Using 1-((3R)-4-t-butyl(dimethyl)silyl)oxy-3-hydroxybutyl)-azide, thetitle compound was prepared by a method similar to the method of Step 2.

(Step 5)

Synthesis of (3S)-4-(t-butyl(dimethyl)silyl)oxybutane-1,3-diamine

To a solution of 379 mg of1-((1S)-1-((t-butyl(dimethyl)silyl)-oxymethyl)-3-triaza-1,2-dien-2-iumylpropyl)azidein 8 ml of methanol, 80 mg of 10% palladium-on-carbon catalyst wasadded, and stirred for an hour in hydrogen atmosphere. Filtering thecatalyst off, the solvent was distilled off under reduced pressure toprovide 306 mg of the title compound.

(Step 6)

Synthesis of (4S)-4-(hydroxymethyl)tetrahydropyrimidine-2(1H)-thione

To a solution of 98 mg of(3S)-4-(t-butyl(dimethyl)silyl)-oxybutane-1,3-diamine in 20 ml ofacetonitrile, 65 mg of tetramethylthiuram monosulfide was added,followed by 6 hours' heating under reflux. Distilling the solvent offunder reduced pressure, the resulting residue was purified on silica gelcolumn chromatography (eluent: hexane/ethyl acetate=1/1). The productwas dissolved in 2 ml of tetrahydrofuran, and to the solution 0.16 ml of1.0 M tetrahydrofuran solution of tetrabutylammonium fluoride was added,followed by an hour's standing at room temperature. The reaction liquidwas diluted with ethyl acetate, washed successively with water andsaturated brine, and dried over anhydrous sodium sulfate. Distililng thesolvent off under reduced pressure, 51 mg of the title compound wasobtained.

(Step 7)

Synthesis of ((4S)-2-thioxohexahydropyrimidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylaceticacid and (4S)-4-(hydroxymethyl)tetrahydropyrimidine-2(1H)-thione, thetitle compound was prepared by a method similar to Step 2 of ReferentialExample 12.

REFERENTIAL EXAMPLE 78 ((4R)-2-thioxohexahydropyrimidin-4-yl)methyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using methyl 2-((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)acetate, the titlecompound was prepared by a method similar to Referential Example 77.

REFERENTIAL EXAMPLE 79 2-Thioxohexahydropyrimidin-5-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate

Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylaceticacid and 5-hydroxytetrahydropyrimidine-2(1H)-thion (cf. JP-Hei01(1989)-128970A), the title compound was prepared by a method similar toStep 2 of Referential Example 12.

FORMULATION EXAMPLE 1

The compound of Example 1, 0.1 g, was dissolved in 900 ml of isotonicsodium chloride solution. Further isotonic sodium chloride solution wasadded to make the total amount 1000 ml, and the solution was given asterile filtration through a membrane filter of 0.25 μm in pore size.One (1) ml each of the solution was poured in sterilized ampoules toprovide a liquid inhalant.

FORMULATION EXAMPLE 2

Ten (10) g of the compound of Example 1 was homogeneously mixed with 70g of lactose, and 100 mg of the mixed powder was filled in an exclusivepowder inhaler, to provide a powder inhalant (400 μg per inhalation).

INDUSTRIAL APPLICABILITY

Because those compounds of the present invention exhibit selectiveantagonism to muscarine M₃ receptors, they have little side effect andare safe. They exhibit excellent pharmacological effect and prolongedaction also in inhalation therapy, and hence are useful as treatingagents for diseases of respiratory organs.

1. A compound which is represented by the following general formula (I):

wherein A is represented by the following formula (a₂):

wherein k signifies 0, 1 or 2; R²¹ and R³¹ signify, independently ofeach other, a lower alkyl; and X signifies an anion; Ar signifies aryloptionally having substituent(s) selected from the group consisting ofhalogen, lower alkyl, lower alkenyl and lower alkoxy; and R¹ signifies afluorine-substituted C₄-C₆ cycloalkyl optionally having hydroxylgroup(s); or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, in which R¹ is fluorine-substituted cyclopentylgroup.
 3. The compound according to claim 2, in which R¹ is3,3-difluorocyclopentyl group.
 4. The compound according to claim 1, inwhich k is
 0. 5. The compound according to claim 1, in which both R²¹and R³¹ are methyl.
 6. The compound according to claim 1, in which Ar isa phenyl group having a substituent selected from the group consistingof halogen, lower alkyl, lower alkenyl and lower alkoxy.
 7. The compoundaccording to claim 6, in which Ar is 4-chlorophenyl.
 8. A compound whichis represented by the following general formula (I):

wherein A is represented by the following formula (b₂):

wherein m signifies 0, 1 or 2; R⁶ signifies hydrogen, lower alkyl or agroup represented by —N(R⁸)R⁹; and R⁸ and R⁹ signify, independently ofeach other, hydrogen or lower alkyl; Ar signifies aryl optionally havingsubstituent(s) selected from the group consisting of halogen, loweralkyl, lower alkenyl and lower alkoxy; and R¹ signifies afluorine-substituted C₄-C₆ cycloalkyl optionally having hydroxylgroup(s); or a pharmaceutically acceptable salt thereof.
 9. The compoundaccording to claim 8, in which R¹ is fluorine-substituted cyclopentylgroup.
 10. The compound according to claim 9, in which R¹ is3,3-difluorocyclopentyl group.
 11. The compound according to claim 8, inwhich m is 1 or
 2. 12. The compound according to claim 8, in which R⁶ ishydrogen.
 13. The compound according to claim 8, in which Ar is a phenylgroup optionally having a substituent selected from the group consistingof halogen, lower alkyl, lower alkenyl and lower alkoxy.
 14. Thecompound according to claim 13, in which Ar is unsubstituted phenyl. 15.A compound which is represented by the following general formula (I):

wherein A is by the following formula (a_(p2)):

wherein k signifies 0, 1 or 2; and R²⁰ signifies hydrogen or a loweralkyl optionally having substituent(s) selected from the groupconsisting of phenyl and cycloalkyl; Ar signifies aryl optionally havingsubstituent(s) selected from the group consisting of halogen, loweralkyl, lower alkenyl and lower alkoxy; and R¹ signifies afluorine-substituted C₄-C₆ cycloalkyl optionally having hydroxylgroup(s); or a pharmaceutically acceptable salt thereof.
 16. Thecompound according to claim 15, in which R¹ is a fluorine-substitutedcyclopentyl group.
 17. The compound according to claim 16, in which R¹is 3,3-difluorocyclopentyl group.
 18. The compound according to claim15, in which k is
 0. 19. The compound according to claim 15, in which Aris phenyl which has substituent(s) selected from the group consisting ofhalogen, lower alkyl, lower alkenyl and lower alkoxy.
 20. The compoundaccording to claim 19, in which Ar is 4-chlorophenyl.
 21. Apharmaceutical composition comprising the compound according to claim 1,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable adjuvant.
 22. The composition according toclaim 21, which is in the form of an inhalant.
 23. A pharmaceuticalcomposition comprising the compound according to claim 8, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable adjuvant.
 24. The composition according toclaim 23, which is in the form of an inhalant.